Chronic pelvic pain and menorrhagia: Assessing treatment effectiveness

Part One: Chronic Pelvic Pain Chapter 2 ......................................................................................................................19 Chronic pelvic pain in women Chapter 3 ......................................................................................................................35 Laparoscopic uterine nerve ablation: A survey of gynaecological practice in the UK Chapter 4 ......................................................................................................................43 Study protocol - A randomised controlled trial to assess the efficacy of Laparoscopic Uterosacral Nerve Ablation (LUNA) in the treatment of chronic pelvic pain: the trial protocol ISRCTN41196151 Chapter 5 ......................................................................................................................61 Laparoscopic Uterosacral Nerve Ablation (LUNA) for alleviating Chronic Pelvic Pain: a Randomized Trial Chapter 6 ......................................................................................................................77 Meta-analysis using individual patient data from randomised trials to assess the effectiveness of laparoscopic uterosacral nerve ablation in the treatment of chronic pelvic pain: a proposed protocol Chapter 7 ......................................................................................................................87 Individual patient data meta-analysis of randomised evidence to assess the effectiveness of laparoscopic uterosacral nerve ablation in chronic pelvic pain Chapter 8 ....................................................................................................................103 Psychological Therapies for Chronic Pelvic Pain: Systematic review of Randomized Controlled Trials Part Two: Heavy Menstrual Bleeding Chapter 9 ....................................................................................................................117 Hysterectomy, endometrial destruction and Mirena® for heavy menstrual bleeding: A systematic review and individual patient data meta-analysis Chapter 10 ..................................................................................................................141 Second generation endometrial ablation techniques for heavy menstrual bleeding: network meta-analysis Chapter 11 ..................................................................................................................163 The measurement properties of the menorrhagia multi-attribute quality-of-life scale: a psychometric analysis Chapter 12 ..................................................................................................................173 Summary and Discussion Samenvatting .............................................................................................................182

...............................................................................................................189 Authors’ affiliations ...................................................................................................193 Dankwoord (Acknowledgements) ............................................................................195 Curriculum vitae ........................................................................................................ 197 9 Chapter 1

10 Chapter 1 Chronic pelvic pain Chronic pelvic pain is described in many ways. 1 The most frequently cited definition is cyclical or non-cyclical pain in the lower abdomen or pelvis, of at least six months’ duration, occurring continuously or intermittently, that causes functional disability or limits activities of daily living. Chronic pelvic pain (CPP) has a major impact on health-related quality of life, work attendance and productivity,2 and health care utilization, accounting for 40% of referrals for diagnostic lapa- roscopy,3 and is an important contributor to health care expenditure.4 Chronic pelvic pain can be a symptom and also a syndrome in its own right when underlying pa- thology has been excluded, which may be termed idiopathic CPP . It may encompass dyspareu- nia, dyschesia, dysuria, or dysmenorrhoea, but it can also be independent of these symptoms. There are several underlying aetiological factors which may overlap, including endometriosis, chronic pelvic inflammatory infection, adhesions, irritable bowel syndrome, interstitial cystitis, and pelvic congestion syndrome.5 Analgesics are often the first line of management, and women often try to manage their pain with over the counter painkillers before consulting with their general practitioner. Pharmaceuti- cal approaches considered first include the combined oral contraceptive pill, progestogens or gonadotropin-releasing hormone agnosists, yet there are very few randomised data to support their use in idiopathic chronic pelvic pain. Methoxyprogesterone acetate provides more improve- ment in pain scores than placebo at 3 months (OR: 2.64, 95%CI 1.33 to 5.25; p=0.005, n=146) which is sustained to 6 months whilst on treatment. No improvement in pain scores was seen in a further small trial of the selective serotonin uptake inhibitor sertraline compared to placebo. 7 The combined oral contraceptive pill is frequently prescribed. Only 20-25% of patients respond to conservative treatment.8 Neuropathic pain treatments are the focus of ongoing investigations following initial promising results,9 although there is no evidence to suggest CPP is neuropathic in origin. Given that the symptoms experienced are chronic, varied and non-specific, a differential diag- nosis in chronic pelvic pain can be hard to establish and women often present to health care providers repeatedly. This wastes both the patients’ time and NHS resources. The diagnosis of endometriosis may be delayed by over 8 years after first presentation with CPP symptoms, 10,11 potentially demoralising the patient and missing the opportunity to improve their life quality through early effective treatment, and may provoke women to seek having a hysterectomy with Chapter 1 11 its inherent risks and consequences. The Royal College of Obstetricians and Gynaecologists guidelines provide a number of suggested initial investigations, including history, microbiological screening and vaginal examination, all with weak evidence for utility. 12 If no cause of the pain is found, gynaecologist frequently perform a diagnostic laparoscopy. As diagnoses emerge through careful history and examination and directed investigation, so do treatment strategies. These should be tailored to the needs of individual patients as, whatever the cause, chronic symptoms need long term management. Surgical treatments tend to focus on the organic causes of pelvic pain. Laparoscopic vaporisation or excision of endometriotic lesions is effective in reducing pain.11 Division of intraperitoneal adhesions is of unclear benefit. 7 Interruption of the Lee-Frankenhauser sensory nerve plexuses by laparoscopic uterosacral nerve ablation was thought to alleviate pain, based on mainly observational data.14 A multidisciplinary approach has been advocated 15 and fits with the biopsychosocial model of pain. Counselling, psychotherapy and attempts to provide reassurance using laparoscopy are employed. Whilst less invasive, psychological approaches are time consuming and may not be acceptable to all women. Trials of cognitive behavioural therapy have been favourable in other chronic pain conditions, but evidence for psychological interventions within chronic pelvic pain is lacking. Heavy menstrual bleeding Heavy menstrual bleeding is another common problem that can significantly impact on women’s lives, and burden individuals and healthcare systems. 16 With an annual community prevalence of 25%,16 HMB accounts for 20% of gynecologist consultations in the UK,18 over 5% of women aged 30-49 consult general practitioners each year in the UK with this problem.18 Rates of surgi- cal procedures for HMB are 14.3 per 10,000 in the UK.19 There is discordance between women’s subjective experience of menstruation, actual menstrual blood loss, 20 and clinicians’ assessment.21 Only about half of women presenting to health provid- ers with heavy menstrual bleeding have blood loss greater than the traditional clinical threshold of 80 ml per cycle considered as heavy menstruation.20 A shift in emphasis away from menstrual blood loss to a more patient-centered definition, to define heavy menstrual bleeding as that sig- nificant as to interfere with women’s physical, emotional and social life, is now advocated, as are the use of patient reported outcomes. 22

12 A range of non-hormonal and hormonal medical treatments are available as first line therapy for women presenting with heavy menstrual bleeding in primary care. For over a decade, the levonorgestrel-releasing intrauterine system (LNG-IUS; [Mirena ®]) has been available for heavy menstrual bleeding. Although developed as a contraceptive, it also reduces menstrual blood loss. 21 In 2007, UK guidance 22 introduced the option of LNG-IUS for heavy menstrual bleeding based on limited evidence.24 Hysterectomy offers a definitive treatment for heavy menstrual bleeding and guarantees amenor- rhoea, but it is particularly invasive and carries significant morbidity.25 It is also expensive – due to the need for general anaesthesia, prolonged hospital stay and delayed recovery. Endometrial ablative techniques aimed at destruction of the functionally active endometrium, along with some of the underlying myometrium, 26 offer a conservative surgical alternative. The first generation ablative techniques, including endometrial laser ablation,27 transcervical resection of the endometrium 28 and rollerball endometrial ablation, were all endoscopic procedures. Al- though they do not guarantee amenorrhoea, their effectiveness in comparison with hysterectomy has been demonstrated in a number of randomised controlled trials. 29-34 However, first genera- tion ablative techniques carry some risks including uterine perforation, cervical laceration, false passage creation, haemorrhage, sepsis and bowel injury. 35,36 Second generation ablative techniques represent simpler, quicker and potentially more efficient options of treating heavy menstrual bleeding, which require less skill on the part of the operator. Second generation techniques employ fluid filled thermal balloons, high temperature saline irriga- tion, 3D bipolar radiofrequency or microwave energy, freezing or photodynamic therapy to cause endometrial destruction. Complications associated with second generation techniques include equipment failure, uterine infection, perforation, visceral burn, bleeding and cyclical pain.37 These procedures appear to be as effective as first generation ablative techniques in a limited number of randomised trials, 37 and some have the added benefit of being performed under lo- cal anaesthetic.38 However, some women treated by endometrial ablation will eventually require repeat ablation or hysterectomy. A proportion of women will also develop subsequent problems such as post surgical adhesions and pelvic floor dysfunction which may lead to further hospital treatment and surgery. Chapter 1 13 Aims of the thesis To provide an overview of the treatments for chronic pelvic pain and of the interventions for heavy menstrual bleeding. Specific questions: • What is the effectiveness of LUNA for chronic pelvic pain? • Are there any subgroups of women who may benefit from LUNA? • What is the current evidence for psychological treatments for chronic pelvic pain? • What is the relative effectiveness of hysterectomy, endometrial destruction techniques and the levonorgestrel releasing intra-uterine system for heavy menstrual bleeding? • What is the relative effectiveness of different second generation endometrial ablation techniques? Outline of the thesis Part One: Chronic Pelvic Pain Chapter 2 reviews the current thinking and evidence base for diagnostic tests and medical, surgical and psychological therapies. Chapter 3 illustrates the situation regarding use of laparoscopic uterosacral nerve ablation (LUNA) in the UK, presenting the results of a survey of clinicians. Chapter 4 describes the protocol for the LUNA randomised controlled trial, detailing the out- comes, analytical methods and practicalities of the trial. Chapter 5 evaluates the clinical effectiveness of LUNA in alleviating chronic pelvic pain in a large randomised controlled trial. Chapter 6 describes the protocol for an individual patient data meta-analysis of five randomised LUNA trials. Chapter 7 presents results from the individual patient data meta-analysis, whereupon data from are subject to further subgroup analyses.

14 Chapter 8 contains a systematic review of the few psychological treatments for chronic pelvic pain. Part Two: Heavy Menstrual Bleeding Chapter 9 describes the results of an individual patient data meta-analysis of the clinical effec- tiveness of hysterectomy, endometrial destruction and the levonorgestrel releasing intra-uterine system. Chapter 10 extends the previous review to by undertaking an indirect comparison of the relative effectiveness of the different types of second generation endometrial destruction techniques. Chapter 11 examines the measurement properties of a patient reported questionnaire assessing the impact of heavy menstrual bleeding on women’s lives. Chapter 12 summarises the previous chapters and describes the results from the studies in this thesis in the context of the current literature. Unanswered questions, implications for clinical prac- tice and directions for future research are discussed and the main conclusions are described. Chapter 1 15

1 Williams RE, Hartmann KE, Steege JF. Documenting the current definitions of chronic pelvic pain: implications for research. Obstet Gynecol 2004 Apr;103(4):686-91. 2 Sundell G, Milsom I, Andersch B. Factors influencing the prevalence and severity of dys- menorrhoea in young women. BJOG 1990 Jul;97(7):588-94. 3 Howard FM. The role of laparoscopy in chronic pelvic pain: promise and pitfalls. Obstet Gynecol Surv 1993;48(6):357-87. 4 Winkel CA. Modeling of medical and surgical treatment costs of chronic pelvic pain: New paradigms for making clinical decisions. Managed Care 1999;5(5):S276-S290. 5 Latthe P , Mignini L, Gray R, Hills RK, Khan KS. Factors predisposing women to chronic pelvic pain: systematic review. BMJ 2006;332(7544):749-55. 6 Henzl MR. Dysmenorrhoea: achievements and challenges. Sexual Medicine Today 1985;9:8-12. 7 Stones W, Cheong YC, Howard FM. Interventions for treating chronic pelvic pain in wom- en. Cochrane Database of Systematic Reviews 2005;2. 8 Engel CC, Jr., Walker EA, Engel AL, Bullis J, Armstrong A. A randomized, double- blind crossover trial of sertraline in women with chronic pelvic pain. J Psychosom Res 1998;44(2):203-7. 9 Sator-Katzenschlager SM, Scharbert G, Kress HG, Frickey N, Ellend A, Gleiss A, et al. Chronic pelvic pain treated with gabapentin and amitriptyline: a randomized controlled pilot study. Wien Klin Wochenschr 2005;117(21-22):761-8. 10 Ballard K, Lowton K, Wright J. What’s the delay? A qualitative study of women’s experi- ences of reaching a diagnosis of endometriosis. 2006;86(5):1296-301. 11 Hadfield R, Mardon H, Barlow D, Kennedy S. Delay in the diagnosis of endometriosis: a survey of women from the USA and the UK. Hum Reprod 1996;11(4):878-80. 12 RCOG Guidelines and Audit Committee. The initial management of chronic pelvic pain. Royal College of Obstetricians and Gynaecologists; 2005. Guideline No.41. 13 Jacobson TZ, Duffy J MN, Barlow D, Koninckx PR, Garry R. Laparoscopic surgery for pelvic pain associated with endometriosis. Cochrane Database of Systematic Reviews 2009;4. 14 Khan KS, Khan SF, Nwosu CR, Dwarakanath LS, Chien PFW. Laparoscopic uterosacral nerve ablation in chronic pelvic pain: An overview. Gynaecol Endosc 1999;8(5):257-65. 15 Stones RW, Price C. Health services for women with chronic pelvic pain. J R Soc Med 2002;95(11):531-5. 16 Frick KD, Clark MA, Steinwachs DM, Langenberg P , Stovall D, Munro MG, et al. Financial and quality-of-life burden of dysfunctional uterine bleeding among women agreeing to obtain surgical treatment. Womens Health Issues 2009;19(1):70-8.

16 17 Shapley M, Jordan K, Croft PR. An epidemiological survey of symptoms of menstrual loss in the community. Practice 2004;54(502):359-63. 18 Coulter A, Bradlow J, Agass M. Outcomes of referrals to gynaecology outpatient clinics for menstrual problems: An audit of general practice records. BJOG 1991;98:789-96. 19 Cromwell DA, Mahmood TA, Templeton A, van der Meulen JH. Surgery for menorrhagia within English regions: variation in rates of endometrial ablation and hysterectomy. rit Ob- stet Gynaecol 2009;116(10):1373-9. 20 Higham JM, Shaw RW. Clinical associations with objective menstrual blood volume. Eur J Obstet Gynecol Reprod Biol 1999;82(1):73-6. 21 Warner P , Critchley HO, Lumsden MA, Campbell-Brown M, Douglas A, Murray G. Refer- ral for menstrual problems: cross sectional survey of symptoms, reasons for referral, and management. BMJ 2001;323(7303):24-8. 22 National Collaborating Centre for Women’s and Children’s Health. Heavy Menstrual Bleeding. London: Royal College of Obstetricians and Gynaecologists; 2007. Report No.: CG44. 23 Endrikat J, Vilos G, Muysers C, Fortier M, Solomayer E, Lukkari-Lax E. The levonorg- estrel-releasing intrauterine system provides a reliable, long-term treatment option for women with idiopathic menorrhagia. Arch Gynecol Obstet 2012;285(1):117-21. 24 Stewart A, Cummins C, Gold L, Jordan R, Phillips W. The effectiveness of the lev- onorgestrel-releasing intrauterine system in menorrhagia: a systematic review. BJOG 2001;108(1):74-86. 25 Lethaby A, Sheppard S, Cooke I, Farquhar C. Endometrial resection and abation versus hysterectomy for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 1999;(2). 26 Duffy S, Reid P C, Sharp F. In-vivo studies of uterine electrosurgery. BJOG 1992;99(7):579- 82. 27 Goldrath M H, Fuller TASS. Laser photovaporisation of endometrium for the treatment of menorrhagia. Am J Obstet Gynaecol 1981;140:14-9. 28 Magos A, Baumann R, Turnbull A C. Transcervical resection of the endometrium in wom- en with menorrhagia. BMJ 1989;298:1209-12. 29 Gannon M, Holt E M, Fairbank J, Fitzgerald M, Milne M A, Crystal A M, et al. A ran- domised control trial comparing endometrial resection and abdominal hysterectomy for the treatment of menorrhagia. BMJ 1991;303:1362-4. 30 Dwyer N, Hutton J, Stirrat G M. Randomised controlled trial comparing endometrial re- section with abdominal hysterectomy for the surgical treatment of menorrhagia. BJOG 1993;100:237-43. 31 Pinion S B, Parkin D E, Abramovich D R, Naji A, Alexander D A, Russell I T Randomised trial of hysterectomy, endometrial laser ablation, and transcervical endometrial resection for dysfunctional uterine bleeding. BMJ 1994;309(6960):979-83. Chapter 1 17 32 O’Connor H, Broadbent J A, Magos A L, McPherson K. Medical Research Council ran- domised trial of endometrial resection versus hysterectomy in the management of menor- rhagia. Lancet 1997;349(9056):891-901. 33 Crosignani P G, Vercellini P , Apolone G, De Giorgi O, Cortesi I, Meschia M. Endometrial resection versus vaginal hysterectomy for menorrhagia: long-term clinical and quality-of- life outcomes. Am J Obstet Gynaecol 1997;177(1):95-101. 34 Cooper K G, Jack S A, Parkin D E, Grant A M. Five-year follow up of women randomised to medical management or transcervical resection of the endometrium as treatment for heavy menses. BJOG 2001;108:1222-8. 35 Overton C, Hargreaves J, Maresh M. A national survey of the complications of endome- trial destruction for menstrual disorders: the MISTLETOE study. Minimally Invasive Surgi- cal Techniques- Laser, EndoThermal or Endoresection. BJOG 1997;104(12):1351-9. 36 Scottish Hysteroscopy Audit Group. A Scottish audit of hysteroscopic surgery for menor- rhagia: complications and follow up. BJOG 1995;102(3):249-54. 37 Lethaby A, Hickey M, Garry R, Penninx J. Endometrial resection / ablation techniques for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2009. 38 Clark TJ, Samuel N, Malick S, Middleton LJ, Daniels J, Gupta JK. Bipolar radiofrequency compared with thermal balloon endometrial ablation in the office: a randomized controlled trial. Obstet Gynecol 2011 Jan;117(1):109-18.

18 19 Chapter 2 Chronic pelvic pain in women 20 Chapter 2 Summary points • Chronic pelvic pain is a common and debilitating condition • Women with chronic pelvic pain want to be taken seriously and attach a high value to identifying a cause for their pain • No organic cause is found on laparoscopy in at least a third of women with chronic pelvic pain, and patients should be made aware of this before they consent to investigations • Psychological symptoms, such as anxiety and depression, are frequently present • Gynaecological treatment for chronic pelvic pain is often unsatisfactory even when directed by an identified cause • A multidisciplinary approach is thought to be essential for effective management Chronic pelvic pain in women is a debilitating condition that impairs quality of life. Studies using various definitions estimated its prevalence ranges from 2.1% to 24% of the female population worldwide. 1 It is a common presentation in UK primary care, with 38 per 1000 women affected annually—a rate comparable to those of asthma (37 per 1000) and back pain (41 per 1000). 2 Because pelvic pain is associated with conditions such as endometriosis and interstitial cystitis, a diagnosis is often difficult to establish, leading to a delay in appropriate treatment. Social and psychological factors are strongly associated with chronic pelvic pain, so tailored, effective treat- ment can be challenging to provide. Sources and selection criteria We searched EMBASE and Medline for articles with titles that included the keywords “chronic pelvic pain” with the limits “meta-analysis, review and randomised controlled trial”. We restricted the search to articles published in English in the past five years. We identified all systematic reviews and trial citations in the Cochrane Library under the MeSH terms pelvic pain and dys- menorrhoea. Articles of interest cited in these papers were identified. Finally we reviewed pub- lished clinical guidelines from international pain associations and gynaecological societies and searched the National Guidelines Clearing House. Chapter 2 21 What is chronic pelvic pain and who gets it? Chronic pelvic pain is described in many ways.3 The most frequently cited definition is cyclical or non-cyclical pain in the lower abdomen or pelvis, of at least six months’ duration, occurring con- tinuously or intermittently, that causes functional disability or limits activities of daily living. 4 The condition is perhaps best seen from a biopsychosocial perspective; organic pathology, beliefs, coping skills, and social interactions all contribute to the woman’s experience of pain. 5 Chronic pelvic pain can be a symptom and also a syndrome in its own right when underlying pathology has been excluded. It may encompass dyspareunia (pain during sexual intercourse), dyschesia (painful bowel motions), dysuria (painful micturition), or exacerbation of dysmenor - rhoea (painful periods), but it can also be independent of these symptoms. Possible pathological causes include endometriosis, chronic pelvic inflammatory infection, adhesions, 6 irritable bowel syndrome, interstitial cystitis, and pelvic congestion syndrome. 7 Pain may also arise from mus- culoskeletal conditions, from pelvic organ prolapse, or from adaptive posture as a result of lower back pain. At diagnostic laparoscopy, a substantial proportion of women with chronic pelvic pain (55% in a recent study) have no obvious pathological cause for their pain; 8 this syndrome is also called idio- pathic chronic pelvic pain. Several neural paths within the pelvis transmit pain from the reproductive organs, 9 but these nerve fibres may also refer pain to somatic receptors and manifest as chronic pelvic pain.10 Changes to inflammatory cytokines observed in patients with interstitial cystitis, irrita- ble bowel syndrome, and vulvar vestibulitis might indicate neurogenic inflammation.11 A review of factors predisposing women to chronic pelvic pain identified that drug or alcohol misuse, miscarriage, heavy periods, previous caesarean section, pelvic pathology, abuse, and psychological comorbidities were associated with a higher risk of non-cyclical pain. 6 Figure 1 summarises these findings using composite categories. Psychological factors affect how people react to and report pain, and they result in coping strategies that can have either a positive or negative effect on wellbeing. Twin studies indicate an aspect of heritability, although this can be accounted for by genetic variance underlying the related conditions of endometriosis, fibroids, dysmenorrhoea, and also somatic distress: no independent genetic factors were identified as unique to idiopathic chronic pelvic pain. 12 Chronic pelvic pain in women 22 Figure 1 Composite forest plot of data from studies of individual risk factors associated with dyspareunia, dysmenorrhea, and non-cyclical pelvic pain6 What are the personal and societal costs of chronic pelvic pain? The negative effect of chronic pelvic pain on women’s general quality of life is substantial. Women with chronic pelvic pain tend to report lower general physical health scores than controls without pain.13,14 Women with chronic pelvic pain describe loss, social isolation, and effects on relation- ships. They have a high incidence of comorbidity, sleep disturbance, and fatigue. A community based study found that 41% of women with chronic pelvic pain had not seen a healthcare provid- er in the previous year, 13 suggesting that most women are coping outside of the system. Pain af- fects daily activities; around 18% of employed women in the UK take at least a day off work each year because of such pain.13 The economic burden to healthcare systems is difficult to establish and no recent data are available. Hospital episode data estimated the direct cost of health care for chronic pelvic pain at £158m (€188m, $237m) with a further £24m in indirect costs in 1992. 15 How is chronic pelvic pain diagnosed? Because the symptoms are varied and non-specific, a differential diagnosis can be hard to es- tablish. The condition is chronic and women present repeatedly over several years. It is important to consider the whole range of possible causes at every new encounter in the general practice or gynaecology clinic, whether first or repeat, bearing in mind the biopsychosocial perspective (Figure 2). A previously diagnosed condition may have recurred (for example, endometriosis) or a new condition may have developed (such as interstitial cystitis or depression in a woman previously diagnosed with endometriosis or idiopathic chronic pelvic pain). A multidisciplinary approach is ideal. Chapter 2 23 Figure 2 Biopsychosocial model of chronic pelvic pain Women with chronic pelvic pain want to feel they are being taken seriously, desire reassurance, and attach importance to having an explanation for their pain. 16 Failure to address these con- cerns can mean a loss of opportunity to improve the patient’s quality of life. 17 The International Pelvic Pain Society recommends the use of body charts, simple visual analogue scales, and the short-form McGill questionnaire. 18 Although these measures may help women to articulate their experience of pain, qualitative research shows that the McGill pain questionnaire does not capture the full range of descriptions women attribute to pain. 19,20 The clinician should explore descriptions and locations of pain with the patient. 21 Enabling the woman to tell her story and consider the causes of pain helps to improve the therapeutic relationship and serves as a positive experience for the woman. 22 By taking a history of the patterns and intensity of pain and its association with gynaecological, urogenital, and bowel symptoms, a potential cause may be revealed. 23,24 Women with endome- triosis report throbbing pain and pain during defecation more frequently that those with idiopathic chronic pelvic pain.21 Symptoms suspicious of pelvic inflammatory disease should prompt a cer- vical swab, although a negative culture does not always exclude the diagnosis. 25 Psychological history is equally important in view of the association between chronic pelvic pain and anxiety and Chronic pelvic pain in women 24 depressive symptoms.6 Routine use of a simple screening questionnaire, such as the two ques- tion Patient Health Questionnaire-2, may help to identify depression. 26 A more sensitive subject to raise is that of physical and sexual abuse. 6 Few valid tools exist to guide questionning 27 and such investigations should always be supported with appropriate counselling services. Physical examination can also inform further testing. For example, tenderness or nodularity of the cul-de- sac and uterosacral ligaments are highly predictive of deep endometriosis,28,29 and tenderness of the uterus to palpation is a non-specific marker for adenomyosis. Pelvic organ prolapse can be assessed and described with the POP-Q system.30 The accuracy of tests used for chronic pelvic pain is affected by the range of target conditions that havedifferent diagnostic standards and criteria. Additionally, a woman may have more than one underlying cause for her symptoms. Women should be made aware that a substantial proportion of women with chronic pelvic pain do not have an identifiable organic cause before consenting to unpleasant and potentially risky investigations. Radiological tests including transvaginal ultrasound and magnetic resonance (MRI) scanning can delineate normal pelvic organs. They can also identify many pathological conditions such as deep infiltrating endometriosis29 and ovarian endometrio- ma,31 adenomyosis,32 adhesions,33 dilated pelvic veins,34 and other soft markers.35 Although its accuracy is not perfect, the use of MRI for the differential diagnosis of chronic pelvic pain has the potential to replace diagnostic laparoscopy in a proportion of women.36,37 Laparos- copy is regarded as the “gold standard”38,39 although many target conditions cannot be diagnosed in this way (for example, ademomyosis). Laparoscopically diagnosable diseases are more common (65%) among women with chronic pelvic pain than in those without such pain (28%).39 Although diagnostic criteria such as perihepatic adhesions in pelvic inflammatory disease40 or typical lesions seen in endometriosis41 are easy to identify, subtle lesions and deep infiltrating endometriosis may be missed, possibly because of a lack of training in laparoscopic diagnosis. The relevant question is not so much whether MRI or laparoscopy is more accurate, but which of the two has a greater effect on treatment decisions. This issue will be the subject of research through our recently funded NIHR health technology assessment project (www.medal.bham.ac.uk). Consumers, and some professionals, may see diagnostic laparoscopy as an invasive, expensive, and overused, and risky procedure. 4 Rates of its use vary greatly across regions42 and its use as the initial test in secondary care is by no means universal.43 The procedure is associated with about a 3% risk of minor complications (for example, nausea and vomiting, shoulder tip pain), a 0.24% risk of unan- ticipated injury causing major complications (such as bowel perforation)—of which two-thirds require laparotomy—and an estimated risk of death of 3.3-8 per 100,000. 44,45 Consent for laparoscopic procedures is often poor, with women being confused as to whether the procedure is diagnostic or therapeutic, and complications are a frequent cause for medical negligence claims. 46 Chapter 2 25 What is the initial therapeutic approach for chronic pelvic pain? Analgesics are often the first line of management, and women often try to manage their pain with over the counter painkillers before consulting with their general practitioner. As diagnoses emerge, so do treatment strategies. These strategies should be tailored to the needs of individual patients, since chronic symptoms, whatever the cause, need long term management and a multimodal approach. The combined oral contraceptive pill is frequently used with good results, despite no direct evidence for efficacy in chronic pelvic pain and limited evidence in dysmenor - rhoea.47 The contraceptive pill can be used in the usual way with monthly cycles or continuously to avoid monthly periods and associated pain.48 Two small randomised controlled trials have as- sessed use of medroxyprogesterone for women with a diagnosis of pelvic congestion syndrome; one factorial trial comparing this treatment with psychotherapy and placebo, and one trial against placebo alone. Medroxyprogesterone alone improved pain scores (odds ratio 2.64, 95% confi- dence interval 1.33 to 5.25, n=146) and self reported improvement (6.81, 95% CI 1.83 to 25.3, n=44) at the end of the four month treatment period, but the benefit was not sustained to nine months later.49,50 For many women, progestogens have side effects, such as weight gain and acne, that may lead to discontinuation. The orally vasoactive lofexidine hydrochloride, which was postulated to affect pain by reducing vasospasms associated with pelvic venous congestion, did not show a benefit in a small placebo controlled trial. 51 Tricyclic antidepressants and venlafaxine provide benefit for neuropathic pain 52 but not lower back pain. 53 Only one small randomised controlled trial of sertraline compared with placebo has been reported for chronic pelvic pain, with no evidence of improvement in pain scores. 54 One randomised controlled trial of gabapentin, which is frequently used for neuropathic pain, assessed this drug either alone or in combination with amitriptyline. Fifty-six women with pain refractory to the nonopioid drug metamizol together with weak opioid tramadol were followed up for 24 months of treatment. All women reported improvements in pain, but gabapentin alone or with amitriptyline was better than amitriptyline alone in the reduction of pelvic pain reported on a visual analogue scale. 55 The method of randomisation was unstated and the trial was not blinded, to allow careful titration of drugs to minimise adverse events, so ideally this result should be substantiated in a larger, higher quality trial. Women with chronic pelvic pain tend to be referred to gynaecology clinics. A multidisciplinary approach has been advocated56 and fits with the biopsychosocial model of pain, but such clinics are few and far between, leading to lack of a holistic approach. One Dutch randomised con- trolled trial lends support to this approach. 57 In the group randomised to standard management, diagnostic laparoscopy was routinely done to exclude organic pelvic pain, which was treated ap- propriately. If no somatic cause could be found psychological therapies were considered. In the Chronic pelvic pain in women 26 group randomised to integrated management, somatic, psychological, dietary, environmental, and physiotherapeutic factors were addressed equally and laparoscopy was not routinely done. The latter group had greater self reported improvement (odds ratio 4.15, 95% CI 1.91 to 8.99), better activities of daily living scores (3.53, 95% CI 1.65 to 7.58), and improved non-pain symp- toms (6.99, 95%CI 3.26 to 14.96), but no difference with the standard group in improvement in the McGill pain score (1.52, 95%CI 0.71 to 3.27). It is difficult to identify which components of the integrated approach are responsible, but trials of cognitive behavioural therapy—which aims to influence dysfunctional emotions, behaviours, and cognitions through a goal-oriented, system- atic procedure—have been favourable in other chronic pain conditions. The role of counselling and psychological therapy is not widely appreciated by gynaecologists, general practitioners, and patients. Meta-analysis of two small randomised controlled trials including 142 women with chronic pelvic pain gave a mean difference in pain scores at least six months after intervention of −1.57 (95% CI −2.53 to −0.61, P<0.00001) in favour of the psychological intervention group. 58,59 Surgical treatments tend to focus on the organic causes of pelvic pain. Laparoscopic vaporisa- tion or excision of endometriotic lesions is effective in reducing pain. 60 Division of intraperitoneal adhesions is of unclear benefit.61,62 Interruption of the Lee-Frankenhauser sensory nerve plexuses by laparoscopic uterosacral nerve ablation was thought to alleviate pain. However, considerable evidence,8 including an individual patient data meta-analysis, 63 now shows that the procedure is not effective in reducing dysmenorrhoea, dyspareunia, or non-cyclical pain. Presacral neurec- tomy has been assessed in primary and secondary dysmenorrhoea 64 and seems to be more effective than uterosacral nerve ablation, but it is associated with a high incidence of later consti- pation and is not widely practiced. What are the recommendations from clinical guidelines? The UK Royal College of Obstetricians and Gynaecologists has produced an algorithm for as- sessment and initial treatment of chronic pain, which was the basis of the information in this review.43 Further guidelines recommend that, if no pathology is seen at laparoscopy, a letter of re- assurance should be offered and the woman contacted for review a year later.65 Guidelines from the European Association of Urology also recommend assessment and treatment of nerve en- trapment and pelvic floor dysfunction through nerve blocks and transcutaneous electrical nerve stimulation for interstitial cystitis. 66 Both UK and American guidelines encourage an empirical trial of gonadotropin releasing hormone agonists for women suspected of endometriosis who do not desire a definitive diagnosis or wish to defer surgical investigation. 67-69 Chapter 2 27 Questions for future research • Analysis of distribution of the underlying causes of chronic pelvic pain • Role of MRI in differential diagnosis of chronic pelvic pain • Estimation of accuracy of individual and combinations of diagnostic tests • High quality assessments of treatment packages, including psychological therapies • Development of a new pain assessment tool to capture the multidimensional experience of pelvic pain • Economic analysis to determine most cost effective diagnosis and management strategies Tips for non-specialists • Let the woman tell her story—taking a good history is important. • Consider gynaecological, urological, bowel, and psychological symptoms • Refer to a gynaecological pain specialist or gynaecologist with access to a multidisciplinary pain team Additional educational resources Resources for healthcare professionals International Association for the Study of Pain (IASP) (www.iasp-pain.org) - IASP brings together scientists, clinicians, health care providers, and policy makers to stimulate and support the study of pain and to translate that knowledge into improved pain relief worldwide International Pelvic Pain Society (www.pelvicpain.org) - United States educational society for healthcare providers. A pelvic pain assessment proforma can be downloaded from the website Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network (www.mappnetwork.org) - collaborative research on urological chronic pelvic pain disorders Resources for patients Pelvic Pain Support Network (www.pelvicpain.org.uk)—charity that provides support, informa- tion, and advocacy for people with chronic pelvic pain, and promotes education and research in chronic pelvic pain amongst health professionals. Endometriosis UK (www.endometriosis-uk.org)—provides information and support and works to increase understanding and awareness. The Gut Trust (www.theguttrust.org)—has a telephone helpline and a web based self manage- ment programme for people with irritable bowel syndrome Chronic pelvic pain in women 28 A patient’s perspective I have suffered with period pain since I was fifteen. I had taken various oral contraceptive pills over the years. Sixteen years later, by chance, a retired doctor noticed that I was using a hot water bottle to ease my period pain, which was unbearable. He told me this was not normal and that it could be endometriosis. Two months later, I was diagnosed with severe endometriosis via laparoscopy. Last September, I had laser surgery by laparoscopy and a levonorgestrel intrauter- ine device was inserted. This procedure did not alleviate the pain but the hormonal treatment has reduced the bleeding. Living with endometriosis is extremely frustrating, especially because the path of diagnosis has been so long. I have always been determined to take charge of my life, but the lack of good quality information has hindered me in being able to do this. Recently I was lucky to be able to attend an international congress on endometriosis, a source of reliable information that has given me some directions in which to exert my efforts: finding the best treatments to manage pain and the best options to boost my emotional wellbeing. Although I am scared, now I am in a better position to manage pain and my whole life, which is being affected at all levels by the severity of my condition. From a member of the Pelvic Pain Support Network. Chapter 2 29

1 Latthe P , Latthe M, Say L, Gulmezoglu M, Khan KS. WHO systematic review of prev- alence of chronic pelvic pain: a neglected reproductive health morbidity. BMC Public Health 2006;6:177. 2 Zondervan KT, Yudkin PL, Vessey MP , Dawes MG, Barlow DH, Kennedy SH. Prevalence and incidence of chronic pelvic pain in primary care: evidence from a national general practice database. BJOG 1999;106:1149-55. 3 Williams RE, Hartmann KE, Steege JF. Documenting the current definitions of chronic pelvic pain: implications for research. Obstet Gynecol 2004;103:686-91. 4 Howard FM. The Role of Laparoscopy in the Chronic Pelvic Pain Patient. Clinical Obstet- rics & Gynecology 2003;46(4):749-66. 5 Engel GL. The need for a new medical model: a challenge for biomedicine. Science 1977;196(4286):129-36. 6 Latthe P , Mignini L, Gray R, Hills RK, Khan KS. Factors predisposing women to chronic pelvic pain: systematic review. BMJ 2006;332:749-55. 7 Beard RW. Pelvic congestion: A functional disorder of the menstrual cycle? In: Maclean AB, Stones RW, Thornton S, editors. Pain in obstetrics and gynaecology London: RCOG Press; 2001. 8 Daniels J, Gray R, Hills RK, Latthe P , Buckley L, Gupta J, et al. Laparoscopic uterosa- cral nerve ablation for alleviating chronic pelvic pain: a randomized controlled trial. JAMA 2009;302:955-61. 9 Wesselmann U, Czakanski PP . Pelvic pain: a chronic visceral pain syndrome. Curr Pain Headache Rep 2001;5(1):13-9. 10 Alsom N, Harrison G, Khan KS, Patwardhan S. Visceral hyperalgesia in chronic pelvic pain. BJOG 2009;116:1551-5. 11 Wesselmann U. Neurogenic inflammation and chronic pelvic pain. World J Urol 2001;19:180-5. 12 Zondervan KT, Cardon LR, Kennedy SH, Martin NG, Treloar SA. Multivariate genetic anal- ysis of chronic pelvic pain and associated phenotypes. Behav Genet 2005;35(2):177-88. 13 Zondervan KT, Yudkin PL, Vessey MP , Jenkinson CP , Dawes MG, Barlow DH, et al. The community prevalence of chronic pelvic pain in women and associated illness behaviour. Br J Gen Pract 2001;51:541-7. 14 Grace V, Zondervan K. Chronic pelvic pain in women in New Zealand: comparative well- being, comorbidity, and impact on work and other activities. Health Care Women Int 2006;27(7):585-99. 15 Davies L, Ganger K, Drummond M, Saunders D, Beard R. The economic burden of in- tractable gynaecological pain. J Obstet Gynaecol 1992;12(S2):54-6. Chronic pelvic pain in women 30 16 Price J, Farmer G, Harris J, Hope T, Kennedy S, Mayou R. Attitudes of women with chronic pelvic pain to the gynaecological consultation: a qualitative study. Brit J Obstet Gynaecol 2006;113(4):446-52. 17 Ballard K, Lowton K, Wright J What’s the delay? A qualitative study of women’s experi- ences of reaching a diagnosis of endometriosis. Fertil Steril 2006;86(5):1296-301. 18 Melzack R. The McGill Pain Questionnaire: Major properties and scoring methods. Pain 1975;1(277):299. 19 Grace VM, MacBride-Stewart S. “How to say it”: women’s descriptions of pelvic pain. Women Health 2007;46(4):81-98. 20 Grace VM, MacBride-Stewart S. ‘Women get this’: gendered meanings of chronic pelvic pain. Health (London) 2007;11(1):47-67. 21 Ballard K, Lane H, Hudelist G, Banerjee S, Wright J. Can specific pain symptoms help in the diagnosis of endometriosis? A cohort study of women with chronic pelvic pain. Fertil Steril 2010;94:20-7. 22 Stones RW, Lawrence WT, Selfe SA. Lasting impressions: influence of the initial hospital consultation for chronic pelvic pain on dimensions of patient satisfaction at follow-up. J Psychosom Res 2006;60(2):163-7. 23 Parsons C.L. Diagnosing chronic pelvic pain of bladder origin. J Reprod Med 2004;49(Sup- pl. 3):235-42. 24 Rome Foundation Inc. Rome III Diagnostic Criteria for Functional Gastrointestinal Disor - ders. Gastroenterology 2006;20(5):1377-90. 25 RCOG Guidelines and Audit Committee. Management of Acute Pelvic Inflammatory Disease. Lonson: Royal College of Obstetricians and Gynaecologists; 2003. Greentop guideline 32. 26 Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two- item depression screener. Med Care 2003;41(11):1284-92. 27 Leserman J, Drossman DA, Li Z. The reliability and validity of a sexual and physical abuse history questionnaire in female patients with gastrointestinal disorders. Behav Med 1995;21(3):141-50. 28 Bazot M, Lafont C, Rouzier R, Roseau G, Thomassin-Naggara I, Darai E. Diagnostic ac- curacy of physical examination, transvaginal sonography, rectal endoscopic sonography, and magnetic resonance imaging to diagnose deep infiltrating endometriosis. Fertil Steril 2009;92(6):1825-33. 29 Hudelist G, Oberwinkler KH, Singer CF, Tuttlies F, Rauter G, Ritter O, et al. Combination of transvaginal sonography and clinical examination for preoperative diagnosis of pelvic endometriosis. Hum Reprod 2009;24(5):1018-24. Chapter 2 31 30 Bump RC, Mattiasson A, Bo K, Brubaker LP , DeLancey JO, Klarskov P , et al. The stand- ardization of terminology of female pelvic organ prolapse and pelvic floor dysfunction. Am J Obstet Gynecol 1996;175(1):10-7. 31 Moore J, Copley S, Morris J, Lindsell D, Golding S, Kennedy S. A systematic review of the accuracy of ultrasound in the diagnosis of endometriosis. Ultrasound Obstet Gynecol 2002;20(6):630-4. 32 Champaneria R, Abedin P , Daniels JP , Balogun M, Khan KS. Ultrasound scan and mag- netic resonance imaging for the diagnosis of adenomyosis: Systematic review comparing test accuracy. Acta Obstet Gynecol Scand 2010; 89(11):1374-84. 33 Katayama M, Masui T, Kobayashi S, Ito T, Sakahara H, Nozaki A, et al. Evaluation of pel- vic adhesions using multiphase and multislice MR imaging with kinematic display. Am J Roentgenol 2001;177(1):107-10. 34 Asciutto G, Mumme A, Marpe B, Koster O, Asciutto KC, Geier B. MR venography in the detection of pelvic venous congestion. Eur J Vasc Endovasc Surg 2008;36(4):491-6. 35 Okaro E., Condous G, Khalid A, Timmerman D, Ameye L, Huffel SV, et al. The use of ultra- sound-based ‘soft markers’ for the prediction of pelvic pathology in women with chronic pelvic pain - Can we reduce the need for laparoscopy? BJOG 2006;113(3):251-6. 36 Cody J, Ascher SM. Diagnostic value of radiological tests in chronic pelvic pain. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14:433-66. 37 Bazot M, Thomassin-Naggara I, Darai E, Marsault C. Imaging of chronic pelvic pain. J Radiol 2008;89(1 Pt 2):107-14. 38 Howard FM. The role of laparoscopy in chronic pelvic pain: promise and pitfalls. Obstet Gynecol Surv 1993;48:357-87. 39 Howard FM. The role of laparoscopy as a diagnostic tool in chronic pelvic pain. Best Pract Res Clin Obstet Gynaecol 2000;14:467-94. 40 Kim JY, Kim Y, Jeong WK, Song S-Y, Cho OK. Perihepatitis with pelvic inflammatory dis- ease (PID) on MDCT: Characteristic findings and relevance to PID. Abdom Imaging 2009; 34(6): 737-742 41 Engemise S, Gordon C, Konje JC. Endometriosis. BMJ 2010;340:c2168. 42 Moses SH, Clark TJ. Current practice for the laparoscopic diagnosis and treatment of endometriosis: A national questionnaire survey of consultant gynaecologists in UK. BJOG 2004;111(11):1269-1272. 43 RCOG Guidelines and Audit Committee. The initial management of chronic pelvic pain. London: Royal College of Obstetricians and Gynaecologists; 2005. Greentop guideline 41. 44 Jansen FW, Kapiteyn K, Trimbos-Kemper T, Hermans J, Trimbos JB. Complications of laparoscopy: a prospective multicentre observational study. BJOG 1997;104(5):595-600. Chronic pelvic pain in women 32 45 Chapron C, Querleu D, Bruhat MA, Madelenat P , Fernandez H, Pierre F, et al. Surgical complications of diagnostic and operative gynaecological laparoscopy: a series of 29,966 cases. Hum Reprod 1998;13(4):867-72. 46 Physician Insurers Association of America. Laparoscopic Injury Study. Rockville, MD. USA: Physician Insurers Association of America; 2000. 47 Wong CL, Farquhar C, Roberts H, Proctor M. Oral contraceptive pill for primary dysmen- orrhoea. Cochrane Database Syst Rev 2009;4 48 Kwiecien M, Edelman A, Nichols MD, Jensen JT. Bleeding patterns and patient accept- ability of standard or continuous dosing regimens of a low-dose oral contraceptive: a randomized trial. Contraception 2003;67(1):9-13. 49 Farquhar CM, Rogers V, Franks S, Pearce S, Wadsworth J, Beard RW. A randomized controlled trial of medroxyprogesterone acetate and psychotherapy for the treatment of pelvic congestion. BJOG 1989;96(10):1153-62. 50 Walton SM, Batra HK. The use of medroxyprogesterone acetate 50 mg in the treatment of painful pelvic conditions: Preliminary results from a multicentre trial. BJOG 1992;12(6 (Supp 2)):S50-S53. 51 Stones RW, Bradbury L, Anderson D. Randomized placebo controlled trial of lofexidine hydrochloride for chronic pelvic pain in women. Hum Reprod 2001;16(8):1719-21. 52 Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database of Sys- tematic Reviews 2010;1. 53 Urquhart DM, Hoving JL, Assendelft-Willem JJ, Roland M, van-Tulder MW. Antidepres- sants for non-specific low back pain. Cochrane Database of Systematic Reviews 2008;1. 54 Engel CC, Jr., Walker EA, Engel AL, Bullis J, Armstrong A. A randomized, double- blind crossover trial of sertraline in women with chronic pelvic pain. J Psychosom Res 1998;44(2):203-7. 55 Sator-Katzenschlager SM, Scharbert G, Kress HG, Frickey N, Ellend A, Gleiss A, et al. Chronic pelvic pain treated with gabapentin and amitriptyline: a randomized controlled pilot study. Wien Klin Wochenschr 2005;117(21-22):761-8. 56 Stones RW, Price C. Health services for women with chronic pelvic pain. J R Soc Med 2002;95:531-5. 57 Peters AA, van Dorst E, Jellis B, van Zurren E, Hermans J, Trimbos JB. A randomized clinical trial to compare two different approaches in women with chronic pelvic pain. Ob- stet Gynecol 1991;77:740-4. 58 Haugstad GK, Haugstad TS, Kirste UM, Leganger S, Klemmetsen I, Malt UF, et al. Mensendieck somatocognitive therapy as treatment approach to chronic pel- vic pain: results of a randomized controlled intervention study. Am J Obstet Gynecol 2006;194(5):1303-10. Chapter 2 33 59 Onwude JL, Thornton JG, Morely S, Lilleyman J, Currie I, Lilford R. A randomised trial of photographic reinforcement during post-operative counselling after diagnostic laparos- copy for plevic pain. BJOG 2004;112:89-94. 60 Jacobson TZ, Duffy-J MN, Barlow D, Koninckx PR, Garry R. Laparoscopic surgery for pelvic pain associated with endometriosis. Cochrane Database of Systematic Reviews 2009;4. 61 Stones W, Cheong YC, Howard FM. Interventions for treating chronic pelvic pain in wom- en. Cochrane Database Syst Rev 2005;2 62 Keltz MD, Gera PS, Olive DL, Keltz MD, Gera PS, Olive DL. Prospective randomized trial of right-sided paracolic adhesiolysis for chronic pelvic pain. J Soc Laparo Surg 2006;10(4):443-6. 63 Daniels JP , Middleton L, Xiong T, Champaneria R, Johnson N, Lichten EM, et al. Individual patient data meta-analysis of randomised evidence to assess the effectiveness of lapa- roscopic uterosacral nerve ablation in chronic pelvic pain. Hum Reprod Update 2010; 6(6):568-76 64 Chen F.P ., Chang S.D., Chu K.K., Soong Y.K. Comparison of laparoscopic presacral neurectomy and laparoscopic uterine nerve ablation for primary dysmenorrhea. J Reprod Med 1996;41(7):463-6. 65 Kennedy S, Bergqvist A, Chapron C, D’Hooghe T, Dunselman G, Hummerlshoj L, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod 2005;20:2698-704. 66 Fall M, Baranowski AP , Elneil S, Engler D, Hughes J, Messelink EJ et al Guidelines on chronic pelvic pain. European Urology 2010;57: 35-48 . 67 American College of Obstetricians and Gynaecologists. Chronic pelvic pain. ACOG Prac- tice Bulletin 51. American College of Obstetricians and Gynaecologists, 2004. 68 RCOG Guidelines and Audit Committee. The investigation and management of endome- triosis. Royal College of Obstetricians and Gynaecologists, 2006. Greentop guideline 24. 69 Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol 1999;93(1):51-8. Chronic pelvic pain in women 34 35 Chapter 3 Laparoscopic uterine nerve ablation: A survey of gynaecological practice in the UK 36 Chapter 3

Objective: To determine the current use of and the indications for laparoscopic uterine nerve ablation (LUNA) in the UK, and to establish practitioners’ views regarding the desirability of a controlled clinical trial to assess the efficacy of LUNA. Setting: Gynaecologists associated with the British Society of Gynecological Endoscopy. Design: A self-administered structured questionnaire was posted to 457 UK gynaecologists. Their surgical practice and willingness to participate in a randomized trial were surveyed. The postal questionnaire was returned by 249 (55% response rate).

The survey indicated that 113 (45%) of the responders performed LUNA. Of these, 86 (76%) carried out LUNA for chronic pelvic pain, 72 (64%) for endometriosis, and 16 (14%) for dyspaurenia/dysmenorrhoea. Diathermy was used as the surgical tool by 66 (59%) gynae- cologists and laser was used by 57 (51%). Of the 113 currently using LUNA, 91 (81%) were willing to enter patients into a proposed clinical trial of LUNA.

Current clinical practice regarding LUNA for pelvic pain is hung in equipoise. This means that the technique has been introduced without reliable evidence of efficacy but opinion regarding its use is not yet solidified. Hence, a rigorous randomized trial of LUNA’s efficacy is urgently needed and is practicable.

Chronic pelvic pain, defined as constant or intermittent, cyclic or acyclic pelvic pain that persists for 6 months or more, 1 has a major impact on health-related quality of life, work productivity and health care utilisation, costing an estimated 158 million pounds per year in the UK.2 Dys- menorrhoea, deep dyspareunia and intermenstrual pain constitute the main symptom complex in chronic pelvic pain, which frequently leads to surgical interventions including laparoscopy.3,4 With recent developments in minimal access surgery, laparoscopic uterosacral nerve ablation (LUNA) is a practicable treatment option at the time of diagnostic laparoscopy in chronic pelvic pain.4 By interrupting pain pathways in the nerve plexuses and ganglia of the uterosacral ligaments LUNA is expected to alleviate pelvic pain.5,6 Chapter 3 37 However, the therapeutic role of this intervention has not been adequately assessed by rigorous clinical research.7 Despite the lack of definitive evidence, many gynaecologists familiar with the operative technique offer LUNA as a therapeutic option to their patients with pelvic pain. This dis- crepancy between evidence and practice induced us to examine current surgical practices re- garding LUNA and to determine practitioners’ willingness to participate in a clinical trial of LUNA.

and results We undertook a self-administered postal survey of gynaecologists associated with the British Society of Gynaecological Endoscopy. In view of declining return rates to mailed questionnaires, we designed our survey strategy to include the factors known to be associated with higher response. 8,9 Questionnaires were posted to 457 gynaecologists. Of these, 249 returned the questionnaires, which gave a 55% response rate. Responses to individual items were missing from some respondents. Table 1 shows the results of the survey. There were 113 (45%) gynaecologists who carried out LUNA. Of these, 86 (76%) performed LUNA for chronic pelvic pain, 72 (64%) for endometriosis, and 16 (14%) for dyspaurenia/dysmenorrhoea. Diathermy was used as the surgical tool by 66 (59%) gynaecologists and laser was used by 57 (51%). More importantly, of the 113 currently using LUNA, 91 (81%) gynaecologists were willing to enter patients into a proposed clinical trial of LUNA.

The generalisability of our findings may be somewhat diminished by the relatively low rate of response to our questionnaire. Although we made all efforts within our means to enhance the return rate, 8,9 we received replies from just 55% of gynaecologists, a rate lower than that reported in other recent sur- veys.10-12 There are several reasons for non-response, including out-of-date addresses, but the main reason might have been that LUNA has been promoted as an effective treatment in endometriosis based on one influential trial.13 This trial was rigorous, but because of its design it was not possible to distinguish whether the treatment effect was caused by the transection of the uterosacral ligaments or by the ablation of the endometriotic lesions. Indeed, subsequent research has shown that LUNA may not have been the main factor alleviating pain in endometriosis. 14 Lack of this information might have led some gynaecologists to believe that further research on LUNA lacks relevance, leading to an un- enthusiastic attitude towards our questionnaire. However, there has been a trend towards reduction in response to questionnaire surveys8 and so our 55% response rate should be considered reasonable and does not invalidate our findings. Survey of LUNA practice 38 Willing to participate n (%) Unlikely to participate n (%) Indications for LUNA Chronic pelvic pain Only 25 (28) 3 (14) + Endometriosis 36 (40) 8 (36) + Other 7 (8) 1 (4) + Endometriosis + other 4 (4) 2 (9) Endometriosis Only 12 (13) 3 (14) + Other 4 (4) 3 (14) Other Only 1 (1) 1 (4) Not recorded 2 (2) 1 (4) Total 91 22 Surgical technique for LUNA Diathermy Only 37 (41) 1 (4) + Laser 10 (11) 6 (27) + Scissors 8 (9) 2 (9) Laser Only 28 (31) 10 (45) + Scissors 1 (1) 0 (0) Scissors Only 3 (3) 0 (0) Not recorded 3 (3) 2 (9) Total 91 22 Table 1 Current UK gynaecological practice concerning laparoscopic uterosacral nerve ablation (LUNA), according to gynaecologist’s willingness to participate in a proposed trial of LUNA Chapter 3 39 The assessment of new surgical interventions requires an initial assessment of safety and practicability followed by a proper randomized evaluation.15 We undertook a systematic literature review concern- ing LUNA,7 which identified only a few publications with evaluative evidence on LUNA. Moreover, this literature consisted largely of observational uncontrolled case series and poor quality controlled studies which could not be regarded as anything more than suggestive evidence. The initial evaluative evidence alone is not sufficient to assess the clinical effectiveness of LUNA for which a larger, prop- erly randomized trial, unconfounded by other variables, is needed. This need has been highlighted in several recent publications.16-18 From our survey, it is disturbing to note that many gynaecologists are performing LUNA as a routine therapeutic procedure when evidence is insufficient to establish efficacy. On the other hand it is encouraging that many gynaecologists wish to participate in a clinical trial. This is a situation where equipoise applies (i.e. the technique has been introduced without definite evidence but opinion regarding its use is not yet solidified) making the need for a trial even more urgent. Encouraged by our survey, we have launched a multi-centre, prospective, blind, randomized con- trolled trial assessing LUNA. Eligible consenting patients are randomly allocated at diagnostic laparos- copy either to LUNA or to no pelvic denervation.19 The main endpoints for assessing the efficacy of LUNA are pain, sexual function and quality of life. Long-term follow up will be undertaken as well as short-term monitoring. This study is being coordinated from the University of Birmingham Clinical Tri- als Unit, and interested gynaecologists are welcome to participate. We await with interest the results of this trial. Survey of LUNA practice 40

1 Vercellini P , Fedele L, Arcani L, Bianchi S, Rognoni MT, Candiani GB. Laparoscopy in the diagnosis of chronic pelvic pain in adolescent women. J Reprod Med1989; 34: 827-30. 2 Davies L, Ganger KF, Drummond M, Saunders D, Beard RW. The economic burden of intractable gynaecological pain. J Obstet Gynaeco 1992; 12: s46-s54. 3 Howard FM. The role of laparoscopy in chronic pelvic pain: promise and pitfalls. Obstet Gynecol Survey 1993; 48: 357-87. 4 Dwarakanath LS, Parsad PS, Khan KS. Role of laparoscopy in the management of chron- ic pelvic pain. Hospital Medicine 1998; 59 (8): 627-31. 5 Frankenhauser G. Die Bewegungenerven der Gebarmutter. Zeitsccrift für Medizin Nat Wiss 1864; 1: 35. 6 Doyle JB, Des Rosiers JJ. Paracervical uterine denervation for the relief of pelvic pain. Clinical Obstetrics and Gynecol 1963; 6: 742-53. 7 Khan KS, Khan SF, Nowsu CR, Dwarakanath LS, Chein PFW. Laparoscopic uterine nerve ablation in chronic pelvic pain: an overview. Gynaecol Endoscopy, 1998; 8: 257-67. 8 McAvoy BR, Kaner EF. General practice postal surveys: a questionnaire too far? BMJ 1996; 313: 732-3. 9 Heywood A, Mudge P , Ring I, Sanson-Fisher R. Reducing systematic bias in studies of general practitioners: the use of a medical peer in the recruitment of general practioners in research. Family Practice 1995; 12: 227-31. 10 McColl A, Smith H, White P , Field J. General practitioners’ perceptions of the route to evidence based medicine: a questionnaire survey. BMJ 1998; 316: 361-5. 11 Olatunbosun OA, Edouard L, Pierson RA. Physicians’ attitudes toward evidence based obstetrics practice: a questionnaire survey. BMJ 1998; 316: 765-6. 12 Gulmezoglu AM, Duley L. Use of anticonvulsants in eclampsia and pre-eclampsia: survey of obstetricians in the United Kingdom and Republic of Ireland. BMJ 1998; 316: 975-6. 13 Sutton CJG, Ewen SP , Whitelaw N, Haines B. Prospective, randomised, double blind controlled trial of laser laparoscopy in the treatment of pelvic pain associated with mini- mal, mild, and moderate endometriosis. Fertil St teril 1994; 62: 696-700. 14 Dover RW, Pooley A, Haines P , Sutton CJG. A prospective randomised double-blind trial of laparoscopic laser uterine nerve ablation in the treatment of pelvic pain associated with endometriosis: a proviaional report. BJOG 1998; 105 (Suppl. 17): 48. 15 Cushcieri A. Minimal access therapy: scope,evaluation and future direction. Healthcare Bulletin 1996; 54: 514-21. 16 Stones RW. Chronic pelvic pain. Personal Assessment in Continuing Education. Review No 97/01. London: Royal College of Obstetricians and Gynaecologists, 1997. Chapter 3 41 17 Stones RW, Mountfield J, Farquhar C. Management of chronic pelvic pain in women. Cochcrane Database of Systematic Reviews. 1998. 18 Porpora MG, Victor G. The role of laparoscopy in the management of pelvic pain in wom- en of reproductive age. Fertil Steril 1997; 68: 765-79. 19 Birmingham Clinical Trials Unit. The LUNA trial. Survey of LUNA practice 42 43 Chapter 4 Study protocol A randomised controlled trial to assess the efficacy of Laparoscopic Uterosacral Nerve Ablation (LUNA) in the treatment of chronic pelvic pain: the trial protocol ISRCTN41196151 44 Chapter 4

Background: Chronic pelvic pain is a common condition with a major impact on health-related quality of life, work productivity and health care utilisation. The cause of the pain is not always obvious as no pathology is seen in 40-60% of the cases. In the absence of pathology there is no established treatment. The Lee-Frankenhauser sensory nerve plexuses and parasympathetic ganglia in the uterosacral ligaments carry pain from the uterus, cervix and other pelvic struc- tures. Interruption of these nerve trunks by laparoscopic uterosacral nerve ablation (LUNA) may alleviate pain. However, the balance of benefits and risks of this intervention have not been reli- ably assessed. LUNA has, nevertheless, been introduced into practice, although there remains controversy regarding indications for LUNA. Hence, there is an urgent need for a randomised controlled trial to confirm, or refute, any worthwhile effectiveness. The principal hypothesis is that, in women with chronic pelvic pain in whom diagnostic laparoscopy reveals either no pathology or mild endometriosis (AFS score ≤ 5), LUNA alleviates pain and improves life quality at 12 months. Methods/ Design: The principal objective is to test the hypothesis that, in women with chronic pelvic pain in whom diagnostic laparoscopy reveals either no pathology or mild endometriosis (AFS score ≤ 5), LUNA alleviates pain and improves life quality at 12 months. A multi-centre, prospective, randomised-controlled-trial will be carried out with blind assessment of outcomes in eligible consenting patients randomised at diagnostic laparoscopy to LUNA (experimental group) or to no pelvic denervation (control group). Postal questionnaires including visual analogue scale for pain (primary outcome), an index of sexual satisfaction and the EuroQol EQ-5D instrument will be administered at 3, 6 and 12 months. The primary assessment of the effectiveness of LUNA will be from comparison of outcomes at the one-year follow-up, although the short, medium and long-term risks and benefits of LUNA will also be evaluated. The sample size for this trial has been estimated as 420 patients in total using the hypothesis that LUNA will alleviate pain symptoms (i.e. reduce pain scores on a VAS) more than no intervention at one-year following diagnostic laparoscopy and taking into consideration 20% loos to follow-up. The intention to treat analysis to address the principal research question will be conducted using the one-year follow-up data. Chapter 4 45

Pelvic pain remains the single most common indication for referral to a gynaecology clinic ac- counting for 20% of all outpatient appointments. 1,2 Five percent of all new appointments are for chronic pelvic pain. 1 It continues to be one of the most difficult and perplexing problems encountered in gynaecology. Pelvic pain has a major impact on health-related quality of life, work productivity and health care utilisation. It is also a major cause of workplace absenteeism.2 An estimated £158 million are spent annually on the management of this condition in the health service. 3 In primary care, the annual prevalence is 38/1000 in women aged 15-73, a rate com- parable to that of asthma (37/1000) and chronic back pain (41/1000).4 An initial troublesome problem in addressing research issues related to pelvic pain is the difficulty in making a definite diagnosis. The following definition is commonly used and will be adopted for our research proposal: constant or intermittent, cyclic or acyclic pain, that persists for 6 months or more and includes dysmenorrhoea, deep dyspareunia and intermenstrual pain.5 An effective treatment for pelvic pain has evaded gynaecologists for centuries. Even today only 20-25% patients respond to conservative management. 6 When such treatment fails, a diagnostic laparoscopy is usually performed.1,7,8 Chronic pelvic pain accounts for up to 40-60% of all diag- nostic laparoscopies.7 The cause of the pain is not always obvious as no pathology is seen in 40-60% of the cases. When definite pathology is found the likely causes are endometriosis (25%) and adhesions (25%).7 There is evidence that negative findings at laparoscopy and follow up with ultrasound will provide reassurance and relief to some patients.9 Randomised trials demonstrate some benefit from ablation of mild and moderate endometriosis10 and from lysis of vascular ad- hesions.11 For patients without obvious pathology there is no established treatment. In recent years, operative laparoscopy has developed rapidly and now makes laparoscopic pelvic denervation a practicable option in the management of chronic pelvic pain. The nerve plexuses and parasympathetic ganglia in the uterosacral ligaments, first described in the last century, 12 and subsequently confirmed,13 carry “pain” from the uterus, cervix and other pelvic structures. The surgical approach to the management of pelvic pain is based on interruption of these nerve trunks, which can be achieved by transection of uterosacral ligaments. LUNA study protocol 46 Figure 1 Pelvic sensory nerve pathways and site for LUNA The transection of the uterosacral ligaments and the nerve plexuses it contains is the simplest of the surgical procedures for pelvic pain. The original work by Doyle described vaginal and abdominal approaches to divide the attachments of the uterosacral ligaments to the cervix. 14,15 With the wider use of minimal access therapy there is a renewed interest in the division of the Frankenhauser nerve plexus in the uterosacral ligaments laparoscopically using lasers or electro- diathermy. In an attempt to relieve patients’ symptoms clinicians frequently perform laparoscopic uterosacral nerve ablation, or LUNA as it is sometimes called. However the efficacy of this proce- dure has not been assessed objectively using methodologically sound research. The Need for the LUNA Trial Health technology assessment in surgical interventions requires an initial evaluation of the safety and stability of new interventions followed by randomised trials. The initial evaluative evidence alone is not sufficient to assess the clinical effectiveness of LUNA for which randomised research remains the gold standard. Chapter 4 47 Evidence from the medical literature In the past, pelvic denervation had been proposed for treatment of chronic pelvic pain, 14 but it has not been widely adopted due to the need for open invasive surgery and the lack of reli- able evidence of benefit. However, recent developments in minimal access surgery now makes LUNA an easily practicable treatment option. Our systematic review has shown that the currently available research evidence on LUNA is inconclusive. 16 Therefore further research is required to generate effectiveness evidence in the form of a high quality randomised controlled trial. This need is also highlighted by the recent Cochrane Reviews 17,18 that recommend rigorous research to assess surgical interventions in chronic pelvic pain. Professional consensus We conducted a survey of UK gynaecologists associated with the British Society of Gynaecologi- cal Endoscopy in 1998 to determine the extent to which LUNA was being used in practice. 19 Our survey indicated that despite the lack of definitive evidence, many gynaecologists familiar with the technique were using LUNA as a therapeutic option. Of the 247 respondents, 108 (44%) of- fered LUNA to patients: 78% for chronic pelvic pain, 66% endometriosis and 18% for dyspaure- nia/ others reasons. Crucially, this survey indicated that 93 of 108 (86%) gynaecologists currently performing LUNA were willing to recruit patients in a randomised trial of LUNA. In this situation equipoise applies (i.e. the technique has been introduced without definite evidence but opinion regarding its use is not yet solidified) making the need for a trial even more urgent. Pilot study We have undertaken a pilot of the LUNA trial with the objective of assessing its feasibility. It has shown acceptability to participants. It has also established trial management procedures, piloted questionnaires, measured compliance and standardised operating procedures. A confidential interim analysis was recently reviewed by an independent data monitoring committee when the first 60 participants had completed 6 months follow-up. The committee’s report regarding compliance and follow-up was encouraging but the recommendation was that a larger study is needed for adequate statistical power in the trial to evaluate LUNA reliably. Research Proposal

1. To test the hypothesis that in women with chronic pelvic pain in whom diagnostic laparos- copy reveals either no pathology or mild endometriosis (AFS score ≤ 5) LUNA alleviates pain and improves life quality at 12 months (principal objective). 2. To test the hypothesis that response to LUNA differs according to the site and cause of the pain by two secondary analyses: (i) women with central pain, (ii) women with no vis- ible pathology. LUNA study protocol 48 3. To explore the variation in LUNA’s effectiveness at different periods of follow-up (3 months, 6 months, 2, 3, 5 and 10 years) 4. To explore any long-term complications of LUNA and to examine the incidence of further gynaecological procedures. Design A multi-centre, prospective, randomised-controlled-trial will be carried out with single blind as- sessment of outcomes in eligible consenting patients randomised at diagnostic laparoscopy to LUNA (experimental group) or to no pelvic denervation (control group). Postal questionnaires including visual analogue scale for pain (primary outcome), an index of sexual satisfaction and the EuroQol 5D-EQ instrument (secondary outcomes) will be administered at 3, 6 and 12 months. The primary assessment of the effectiveness of LUNA will be from comparison of outcomes at the one-year follow-up. The medium and long-term risks and benefits of LUNA will also be evalu- ated by postal questionnaires to the women at 2, 3, 5 and 10 years after laparoscopy. Figure 2 The Laparoscopic Uterosacral Nerve Ablation (LUNA) Trial Schema BMC Women's Health 2003, 3 http://www.biomedcentral.com/1472-6874/3/6 Page 9 of 10 (page number not for citation purposes) Cross Hospital, Wolverhampton, UK); S Keay (Walsgrave Hospital, Coventry, UK); E Shaxted (Northampton Gen- eral Hospital, UK) and J Thornton (City Hospital, Not- tingham, UK) The following centres have obtained ethics approval and await recruitment: A Ali (Darlington Memo- rial Hospital, UK); C Chandler (Billinge Hospital, Wigan, UK); E Downes (Chasefarm Hospital, Enfield, UK); A Hextall (St Albans City Hospital, UK);J Kabukoba (Sand- well Hospital, West Bromwich, UK); M Katesmark (Epsom General Hospital, UK); P. Kirwan (Leicester Gen- eral Hospital, UK); K Louden (Royal Hampshire Hospital, UK);J Moohan (Altnagelvin Area Hospital, UK); S Najja (Queen's Park Hospital, Blackburn, UK); K Olah (War- wickshire General Hospital, UK); M Padwick (Watford General Hospital, UK); P Owen (Stobhill Hospital, Glas- gow, UK) and A Tapp (Royal Shrewsbury Hospital, UK). Additional material

Funding: WellBeing, UK (Charity grant no. CF/371) Data Monitoring Committee: P Brocklehurst, D Braunholtz and JA Jordan

1. M Morris, D O'Niell: Out patient Gynaecology. BMJ 1958, 2:1038. 2. Howard FM: The role of laparoscopy in chronic pelvic pain: promise and pitfalls. Obstet Gynecol Surv 1993, 48:357-387. 3. Stones RW: Chronic pelvic pain. Personal Assessment in Con- tinuing Education. 97/01th edition. London, Royal College of Obstetri- cians and Gynaecologists; 1997. 4. Sundell G, Milsom I, Andersch B: Factors influencing the preva- lence and severity of dys menorrhoea in young women. Br J Obstet Gynaecol 1990, 97:588-594. 5. Davies L, Ganger K, Drummond M, Saunders D, Beard R: The eco- nomic burden of intractable gynaecological pain. J Obstet Gynecol 1992, 12:46-54. 6. Zondervan KT, Yudkin PL, Vessey MP, Dawes MG, Barlow DH, Kennedy SH: Prevalence and incidence of chronic pelvic pain in primary care: evid ence from a nation al general practice database. Br J Obstet Gynaecol 1999, 106:1149-1155. 7. Vercellini P, Fedele L, Arcaini L, Bianchi S, Rognoni MT, Candiani GB: Laparoscopy in the diagnosis of chronic pelvic pain in adoles- cent women. J Reprod Med 1989, 34:827-830. 8. MR Henzl: Dysmenorrhoea; achievements and challenge. Sex Med Today 1985, 9:8-12. 9. Porpora MG, Gomel V: The role of laparoscopy in the manage- ment of pelvic pain in women of reproductive age. Fertil Steril 1997, 68:765-779. 10. G Frankenhauser: Die Bewegungenerven der Gebarmutter. Z Med Nat Wiss 1864, 1:35. 11. Latarjet A Roget P: Le plexus hypogastrique chez la femme. Gynecologie et Obstetrique 1922, 6:225. 12. RM Campbell: Anatomy and physiology of sacrouterine ligaments. Am J Obstet Gynecol 1950, 59:1. 13. JB Doyle: Paracervical uterine denervation by transection of the cervical plexus for th e relief of dysmenorrhoea. Am J Obstet Gynecol 1955, 70:1. 14. Doyle JB Des Rosiers JJ: Paracervical uterine denervation for the relief of pelvic pain. Clinical Obstet Gynecol 1963, 6:742-753. 15. A Cushcieri: Minimal Access Therapy: scope, evaluation and future direction. Health Bull 1996, 54:514-521. 16. Khan KS, Khan SF, Nwosu CR, Dwarakanath LS, Chien PFW: Lapar- oscopic uterosacral nerve ablation in chronic pelvic pain: An overview. Gynaecological Endoscopy 1999, 8:257-265. 17. Wilson ML, Farquhar CM, Sinclair OJ, Johnson NP: Surgical inter- ruption of pelvic nerve pathways for primary and secondary dysmenorrhoea. [Review] [6 refs]. Cochrane Database Syst Rev 2000:CD001896. 18. Stones RW, Mountfield J: Interventions for treating chronic pel- vic pain in women. [update of Cochrane Database Syst Rev. 2000;(2):CD000387 ; 10796713.]. [Review] [15 refs]. Cochrane Database Syst Rev 2000:CD000387. 19. Daniels J, Gray R, Khan K, Gupta J: Laparoscopic uterine nerve ablation: A survey of gynaecological practice in the UK. Gynaecol Endosc 2000, 9:157-159. 20. Unit University of Birm ingham Clinical Trials: The LUNA Trial. http://www luna bham ac uk 2003. The laparoscopic uterosacral nerve ablation (luna) trial schemaFigure 2 The laparoscopic uterosacral nerve ablation (luna) trial schema Identification of eligible patient •Chronic pelvic pain >6mth •Diagnostic laparoscopy planned •Obtain informed consent Follow-up Questionnaire at 3, 6, 12, 24, 36, 60 and 120 months During diagnostic laparoscopy •No obvious pathology •Technically feasible •Randomisation NO LUNALUNA Additional File 1 Appendix A1: Patient information leaflet. Appendix A2: Consent form. Appendix B: Registration and randomisation form. Appendix C: On study form. Appendix D: Post surgery form. Click here for file [http://www.biomedcentral.com/content/supplementary/1472- 6874-3-6-S1.doc] Chapter 4 49 Eligibility All new patients presenting to the gynaecology outpatient clinic with pelvic pain (cyclical or non- cyclical) and/or dyspareunia, and requiring diagnostic laparoscopy for evaluation of these condi- tions, will be invited to participate. Inclusion criteria • Pelvic pain of longer than 6 month duration. • Pain located within the true pelvis or between and below the anterior iliac crests. • Associated functional disability. • Lack of response to medical treatment. • Diagnostic laparoscopy planned. Exclusion criteria • Previous LUNA • Moderate and severe endometriosis (American Fertility Society score >5) • Previous surgery for endometriosis. • Previous surgery for pelvic inflammatory disease. • Previous hysterectomy. • Adnexal pathology. Interventions Diagnostic laparoscopy plus uterosacral nerve ablation (experimental group) or laparoscopy without pelvic denervation (control group). Laparoscopic uterosacral nerve ablation will be carried out in a uniform manner by named sur - geons in each of the participating centres following a common protocol as described in the standard surgical text.20 Routine preparation will be made for a diagnostic laparoscopy with the patient intubated for general anaesthesia. Following pneumoperitonium, a laparoscope will be used to visualise the pelvis. Before embarking on operative laparoscopy an anatomical pelvic assessment will be performed to identify pelvic structures and pathology. At this stage patients with pathology outlined in the exclusion criteria will be excluded. It is expected that around 30% of women will be unsuitable for LUNA at operation and will be ‘registered only’ cases. Eligible patients will be randomised by a telephone call to the Birmingham University Clinical Trials Unit. Clear identification of the uterosacral ligaments is a prerequisite to treatment with lasers or elec- tro-diathermy. The posterior leaf of the broad ligament will be carefully inspected to identify the course of the ureters, which on rare occasions could be particularly close to the uterosacral liga- ments. Care will also be taken to note thin walled pelvic veins, which often lie just lateral to the uterosacral ligaments. If accidentally punctured, they may cause troublesome bleeding requiring LUNA study protocol 50 further endoscopic endocoagulation. The uterosacral ligaments will be identified by manipulation of the uterus in the right and left lateral planes. The ligaments will then be ablated with laser or micropoint electro-diathermy or endocoagulation depending upon the surgeons’ preferences. The ablation will start as close to the posterior aspect of the cervix as possible and continue for a minimum of 1 cm posterolaterally on either side. The aim of the procedure is to destroy the sensory nerve fibres and the secondary ganglia as they leave the uterus and come to lie within the uterosacral ligaments. The safe conduct of operative laparoscopy for LUNA requires the use of two ports, one for deliv- ery of the energy source (laser or diathermy) and another for manipulation. These are in addition to the umbilical port used for the laparoscope itself. In contrast, diagnostic laparoscopy in wom- en with no pathology requires only one port in addition to the umbilical laparoscopic port. This difference in number of ports has potential for introducing bias by compromising patient-blinding to group allocation. A sham incision (see Blinding and Ethical Considerations) in the control group is used to overcome this problem. Randomisation Consenting eligible patients will be randomised to diagnostic laparoscopy plus uterosacral nerve ablation (experimental group) or to no pelvic denervation at the time of diagnostic laparoscopy (control group). Important issues related to randomisation are considered below: Allocation Sequence The subjects will be allocated to groups using a chance procedure, blocking and stratification. 21 Stratified block randomisation will be employed to ensure that there will be nearly equal numbers of patients in the two groups within the prognostic subgroups, even if the study ends prema- turely. Variable block size will be used to avoid any possibility of foreknowledge. Stratified alloca- tion is used so that chance imbalances in the stratification variable do not have an effect on the outcome. Since response to treatment may depend on the surgeons’ technique for laparoscopic uterosacral nerve ablation, analyses will be retrospectively stratified according to the surgeons participating in the trial. Intraoperative randomisation Allocation concealment is a crucial factor in avoiding bias in randomised trials.22 Although it is not possible to blind the surgeon, it is essential to keep the surgeon unaware of the group allocation until after the irrevocable decision to enter the woman into the trial has been made. So, in LUNA, treatment allocation will be issued at diagnostic laparoscopy, after the surgeon has inspected the pelvis and ensured that the patient fulfils all of the inclusion criteria and she does not have any of the exclusion criteria. Women may be randomised or registered into the study by telephoning the toll free Randomisation Line on 0800 953 0274 (+44 121 687 2319 from outside the UK) or Chapter 4 51 by internet randomisation at https://www.trials.bham.ac.uk/luna and clicking on the randomisa- tion button. Passwords for internet randomisation will only be allocated to centres with ethical approval. Following surgery, the surgeon fills in operation details on the post-surgery form. Blinding In the LUNA Trial, patients kept blind to their treatment allocation until the follow-up in the trial is completed. Patients may show a placebo response if they know they have received the ac- tive treatment. The magnitude of placebo effects should not be underestimated. There is clear evidence that inadequacies of blinding in randomisation lead to exaggeration of treatment effect in randomised trials.22 However, there is a potential problem in the maintenance of blinding in the LUNA trial. As men- tioned above, women allocated to have LUNA will have the standard operative laparoscopy with three ports (one 10mm umbilical port and two 5mm lateral ports), whereas women allocated to the control group under normal circumstances would have standard diagnostic laparoscopy with two ports (one 10mm umbilical port and one 5mm lateral or midline port). By noting the different number of incisions some women might become aware of their group allocation and this might alter their response. In order to maintain participant blinding, a sham 5mm skin incision is made superficially in a lateral port site. This approach in avoiding bias due to lack of blinding has been used in a previous trial of laparoscopic nerve ablation, 10 and has received ethical approval in the LUNA trial. A second purpose of blinding is to prevent differences in other aspects of patient management introducing biases affecting the results. The patient’s GP will therefore be kept blind to treatment allocation. Double blinding is not possible in LUNA, however, as the surgeons performing the surgical intervention on the participants will be aware of the group allocation. However, the likeli- hood that this will lead to bias in outcome assessment is low as the outcome assessments in this study will be conducted by patient self-administered questionnaires, avoiding any possible bias from surgeons’ knowledge of group allocation. Endpoints Primary Outcome measure: Visual analogue scale for assessment of pain Pain is difficult to measure, partly because it is accompanied by other sensations and partly because the reaction component affects the judgement of the pain regardless of the intensity of the stimulus. A measure of pain is nevertheless essential to the outcome of this clinical trial. Visual analogue scales (VAS) originally devised as measures of well-being 23 have been success- LUNA study protocol 52 fully adapted to measure pain.24,25 This technique involves use of a 10 cm line on a piece of paper representing a continuum of the participants’ opinion of the degree of pain. It is explained to the participant that the one extreme of the line represents “no pain at all” while the other represents “as much pain as she can possibly imagine”. The subject rates the degree of pain by placing a mark on the line and scale values are obtained by measuring the distance from zero to that mark. Visual analogue scales in the assessment of pain have been established to be reproducible and accurate.25 VAS has commonly been used in measurement of chronic pain. 26 All the studies of LUNA included in systematic reviews so far have used this measure, or a variation on it, for as- sessing outcome. Individual pain scores have sufficient psychometric strengths to be used in chronic pain research involving group comparison designs. 27 Secondary Outcome measures Assessment of sexual function Sexual function is an important aspect of life quality in patients with pelvic pain. Pain itself is an anti-aphrodisiac, and together with discomfort and altered self image, it impacts upon sexual function.28 Its assessment in an objective manner is therefore an important part of the LUNA trial. There are several sexual function instruments, with high levels of reliability, validity and respon- siveness, which yield comparable results across occasions and individuals, making them suitable for monitoring therapeutic progress in randomised research.28 The Sexual Activity Questionnaire (SAQ)29 will replace the Brief Index of Sexual Satisfaction (ISS)30 for the assessment sexual function. The outcome measure has been changed because of poor acceptability and compliance with the ISS. The SAQ has excellent internal consistency and test retest reliability. It also has excellent concurrent and construct validity and has been shown to be acceptable to women in other clinical trials.31 In the questionnaire it will be clearly stated that the measure of sexual function covers material that is sensitive and personal. Participants will be reassured that their responses will be kept completely confidential and that if they do not wish to answer any questions, they will be allowed to leave the questionnaire blank. Health-related quality of life Instrument The EuroQol EQ-5D questionnaire will be used to assess health-related quality of life (HRQL) instruments are becoming powerful tools for outcome assessments in randomised trials. Quality of life instruments assess aspects of patient’s health status usually not grasped by conventional clinical indices; hence, they can be applied as complementary assessments together with VAS and SAQ. Quality of life has to be defined clearly and patient’s perception of normal performance serves a pivotal role in this context. HRQL instruments are administered with questionnaires as- sessing a number of different domains, i.e. areas of behaviour or experience that the instrument is attempting to measure. 32 Chapter 4 53 Resource usage and additional procedures LUNA is a quick, safe and inexpensive procedure for women already undergoing diagnostic laparoscopy. Our hypothesis is about a clinically important effect without an excess of complica- tions. If the hypothesis is confirmed, then any benefits will essentially be “dominant” outweighing the relatively small costs of intervention. Therefore, we do not plan a formal economic evaluation at this stage. However, data on health resource use will be collected partly as efficacy outcome measures (i.e. less need for medical care for pelvic pain indicates greater efficacy), and partly to allow an economic evaluation to be carried out, should significant complications occur. Other measures will include analgesic use, consultations at general practice and hospital, and time off work. Again these are both economic outcomes and indicators of residual pain. Follow-up Postal questionnaires to assess pain and sexual function will be administered at enrolment in the trial and then at 3, 6, 12, 24 and 36 months after laparoscopy. The outcomes at 12 months will be used to address the primary research question. This time interval is chosen because laparos- copy alone has a placebo effect for up to 3-6 months in some patients. 33,34 The 24 and 36 month follow up will be used to monitor medium term effects of the intervention. Existing participants in the trial who consented to 3 years of follow-up will be asked to consent to long-term follow-up (10 years) once they have reached the 3 year follow up time-point. Participants randomised after June 2003 will be asked to consent to 10 years of follow-up at entry. Table 1: LUNA Trial data collection schedule Clinic Theatre Follow up (months/years) 3 6 12 2 3 5 10 Patient information and consent x Eligibility Checklist and Randomisation form x x Enrolment Questionnaire x Surgery Form x Letter to GP x Follow-up Questionnaire x x x x x x x LUNA study protocol 54 Ineligible Patients – follow-up only Women who are ineligible for the LUNA trial because of moderate to severe endometriosis, signif- icant adhesions, significant pelvic inflammatory disease, other significant pathology or those for whom LUNA is not technically feasible should be registered with the Trial Office for follow-up only. The woman should be told that she was not eligible for the trial randomisation, and the reasons why, and asked if she would agree to complete the follow-up questionnaires at 6 and 12 months. This non-random cohort will provide comparative data on the natural history of patients with chronic pelvic pain with significant pathology. Side-effects quantification The centres have been advised to fill an “adverse event form” in case of immediate and delayed complications if any are associated with the procedure. Sample Size and Power Considerations The sample size for this trial has been estimated using the hypothesis that LUNA will alleviate pain symptoms (i.e. reduce pain scores on a VAS) more often than no intervention at one-year following diagnostic laparoscopy. Cohen describes ‘effect sizes’ of 0.2 and 0.5 standard devia- tions (SD) as ‘small’ and ‘medium’. Interim analyses of the pilot study indicate that the SD of the difference in change in VAS scales between LUNA and no pelvic denervation groups will be about 4.0. This corresponds to small and medium effect sizes on VAS of 0.8 and 2.0 respectively and is consistent with other studies of chronic pelvic pain, where clinically important symptom alleviation has been defined as a reduction in pain score of 2 or more. 35 To confirm or refute a small to medium effect of LUNA (0.3 SD difference or 1.2 VAS points), based on α=0.05 and ß=0.2 (80% power), 175 participants in each group (i.e. 350 participants in total) will be required. Considering a 20% loss to follow-up, the sample size is inflated to 220 participants in each group (i.e. 440 participants in total). Stratification Variables Randomisation will be conducted using minimisation, stratified by the four variables: a. Presence or absence of some minimal pathology (minimal endometriosis ± ablation; ad- hesions requiring adhesionolysis only; minimal pelvic inflammatory disease) b. Site of pain (presence of central pain or not) c. Parity of the woman (nulliparous or parous) d. Whether the woman is sexually active or not The first two variables form the prespecified subgroup analyses, and the other two variables are included as having impact on dysmennorhoea and dyspareunia respectively. Chapter 4 55 Data Analysis Type of analysis Intention to Treat The main analysis to address the principal research questions will be undertaken using the one- year follow-up data. The mean differences in VAS pain scores; sexual satisfaction and life quality scores in the two groups will be comparing using a two-sample t-test. The rates of women with clinically significant (2 VAS point) alleviation of pain symptoms will also be compared produc- ing a Peto odds ratio estimate with 95% confidence intervals (Mantel-Haenzel test). Baseline characteristics of the participants enrolled in the two groups will be compared to ensure that randomisation has produced comparable groups of participants.) The use of additional treatment (co-intervention) for pelvic pain following LUNA or no pelvic denervation will be assessed for any systematic difference between the two groups. Subgroup analyses are limited by statistical power and can produce spurious results particularly if many are undertaken. Our literature review 16 and consultation with gynaecologists,19 suggests that the effectiveness of LUNA may be greater for central compared to non-central pain and if there is no associated pathology. Therefore, we have chosen to limit secondary analyses to these subgroups only. The LUNA trial is powered to detect a small to medium overall difference and if a larger treatment benefit is found then other subgroup analyses will be undertaken, but interpreted appropriately cautiously. The LUNA trial is powered overall at 80% to detect a 0.3 SD difference in effect. Our pilot study shows that 60% of participants have mainly central pain and 70% have no pathology. Hence, in the subgroup with central pain the power will be 80% to detect a 0.4 SD treatment effect. In the subgroup with no pathology the power will be 80% to detect a 0.35 SD treatment effect. Frequency of analyses Interim analysis at completion of 6 months follow-up of the first 60 patients has already been completed as pilot study. Bi-annual analyses of recruitment, compliance and loss to follow-up are being carried out for LUNA Trial Management Committee. An annual interim analysis of effective- ness is done for confidential review by independent Data Monitoring Committee to determine whether the principal question has been answered and to monitor adverse events. Main analyses of effectiveness of LUNA will be done at completion of one year follow up of the total study sam- ple. Additional analysis of long-term effects will be done at two and three-year follow-up points. Ethical considerations When there is uncertainty about the appropriate therapy, clinical trials are the scientifically and ethically best way to resolve this uncertainty and thereby benefit both the individual participants and all others concerned in their care. 36 The need for a “sham” incision in this trial is the main ethical issue and it is required because without it the participants cannot be kept blinded. The LUNA study protocol 56 purpose of blinding is to prevent various biases from affecting the results. The need for blinding in surgical trials has been emphasised in the medical literature,37 and there is empirical evidence that inadequacies of blinding in randomisation lead to exaggeration of therapeutic efficacy in ran- domised trials. 22 Blinding of participants in surgical trials is clearly indicated when the intervention primarily treats symptoms and when the outcomes are based on participants’ own assessments. LUNA is an intervention for treating chronic pelvic pain (a diagnosis based on symptoms) and the outcome assessment is based on participants’ responses on a visual analogue pain scale and quality of life instruments. Hence, blinding through the use of a “sham” incision is justified if bias is to be avoided in the LUNA trial and this approach has been used in a previous trial of LUNA. 10 Ethical approval for the LUNA trial has already been obtained from the West Midlands Multicentre Research Ethics Committee (MREC). Conduct of the Study and Data Management The trial will be coordinated from the University of Birmingham Clinical Trials Unit (BCTU). Each investigating centre will carry out the study in accordance with the study protocol and to the MRC guidelines on Good Clinical Practice in Clinical Research (1998). Patients will be invited to participate if they fulfil all the inclusion criteria and do not have any exclusion criteria. They will be provided with a laparoscopy and LUNA trial information leaflet and signed consent obtained prior to laparoscopy. Consenting patients should be asked to complete the Enrolment Question- naire. The final decision to enrol patients in the trial will depend on the findings at laparoscopy when the surgeon will perform LUNA or not after determining eligibility as shown in Baseline Data and Randomisation Form. At the end of the procedure the surgeon will complete the Post Surgery Form. All three forms for each participant enrolled will be photocopied to keep a record at the participating centre and the originals will be sent to the BCTU. At 3, 6, 12 months after enrolment, the Follow-up Questionnaire will be mailed to the participants with a pre-paid self addressed envelope. Recruitment is expected to take 12 months and follow up for the main endpoints another 12 months. At completion of the main study, further Follow-up Questionnaire will be mailed out at 2, 3, 5 and 10 years. Chapter 4 57

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Z Med Nat Wiss 1864;1:35. (13) Latarjet A, Roget P . Le plexus hypogastrique chez la femme. Gynecol Obstet (Paris) 1922;6:225. (14) Doyle JB. Paracervical uterine denervation by transection of the cervical plexus for the relief of dysmenorrhoea. Am J Obstet Gynecol 1955;70:1. (15) Doyle JB, Des Rosiers JJ. Paracervical uterine denervation for the relief of pelvic pain. Clinical Obstet Gynecol 1963;6:742-53. (16) Khan KS, Khan SF, Nwosu CR, Dwarakanath LS, Chien PFW. Laparoscopic uterosacral nerve ablation in chronic pelvic pain: An overview. Gynaecol Endosc 1999;8(5):257-65. LUNA study protocol 58 (17) Wilson ML, Farquhar CM, Sinclair OJ, Johnson NP . Surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2000. (18) Stones RW, Mountfield J. Interventions for treating chronic pelvic pain in women. Cochrane Database of Systematic Reviews 2000. (19) Daniels J, Gray R, Khan K, Gupta J. Laparoscopic uterine nerve ablation: A survey of gynaecological practice in the UK. Gynaecol Endosc 2000;9(3):157-9. (20) Sutton C, Whitelaw N. Laparoscopic uterosacral nerve ablation for intractable dysmenor- rhoea. In: Sutton C, editor. Endoscopic surgery for gynaecologists.London: WB Saun- ders; 1993. p. 159-63. (21) Zelen M. The randomization and stratification of patients to clinical trials. J Chronic Dis 1974;27(7-8):365-75. (22) Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408-12. (23) Clarke PR, Spear FG. Reliability and sensitivity in the self assessment of wellbeing. Bull Br Psychol Soc 1964;17:55. (24) Bond MR, Pilowsky I. Subjective assessment of pain and its relationship to the administra- tion of analgesics in patients with advanced cancer. J Psychosom Res 1966;10(2):203-8. (25) Revill SI, Robinson JO, Rosen M, Hogg MI. The reliability of a linear analogue for evaluat- ing pain. Anaesthesia 1976;31(9):1191-8. (26) Carlsson AM. Assessment of chronic pain. I. Aspects of the reliability and validity of the visual analogue scale. Pain 1983;16(1):87-101. (27) Jensen MP , Turner JA, Romano JM, Fisher LD. Comparative reliability and validity of chronic pain intensity measures. Pain 1999;83(2):157-62. (28) Jehu D. Sexual dysfunction- a behavioural approach to causation, assessment, and treatment. Toronto: John Wiley and sons; 1979. (29) Thirlaway K, Fallowfield L, Cuzick J. The Sexual Activity Questionnaire: a measure of women’s sexual functioning. Qual Life Res 1996;5(1):81-90. (30) Hudson W. Index of sexual satisfaction. The clinical measurement package: a field man- ual. Chicago: Dorsey Press; 1982. p. 190-1. (31) Stead ML, Crocombe WD, Fallowfield LJ, Selby P , Perren TJ, Garry R, et al. Sexual activ- ity questionnaires in clinical trials: acceptability to patients with gynaecological disorders. BJOG 1999;106(1):50-4. (32) Guyatt GH, Feeny DH, Patrick DL. Measuring health-related quality of life. Ann Intern Med 1993;118(8):622-9. (33) Fedele L, Marchini M, Acaia B, Garagiola U, Tiengo M. Dynamics and significance of placebo response in primary dysmenorrhea. Pain 1989;36(1):43-7. Chapter 4 59 (34) Baker PN, Symonds EM. The resolution of chronic pelvic pain after normal laparoscopy findings. Am J Obstet Gynecol 1992;166(3):835-6. (35) Zullo F, Pellicano M, DeStefano R. Efficacy of Laparoscopic Pelvic Denervation in Central- type Chronic Pelvic Pain: A multicentre study. J Gynecol Surg 1996;12:35-40. (36) Chalmers T. The clinical trial. Milbank Memorial Fund Quarterly 1981;59:339-42. (37) Johnson AG, Dixon JM. Removing bias in surgical trials. BMJ 1997;314(7085):916-7. LUNA study protocol 60 61 Chapter 5 Laparoscopic Uterosacral Nerve Ablation (LUNA) for alleviating Chronic Pelvic Pain: a Randomized Trial 62 Chapter 5

Context Chronic pelvic pain (CPP) is a common condition with a major impact on health-related quality of life, work productivity and health care use. Operative interruption of nerve trunks in the utero- sacral ligaments, believed to carry pain from the uterus and cervix, by laparoscopic uterosacral nerve ablation (LUNA) is a treatment option for patients with chronic pelvic pain.

To assess the effectiveness of LUNA in patients with chronic pelvic pain. Design, Setting, and Participants Randomized controlled trial of 487 women with chronic pelvic pain lasting longer than 6 months without or with minimal endometriosis, adhesions, or pelvic inflammatory disease, who were recruited to the study by consultant gynecological surgeons from 18 UK hospitals between Feb- ruary 1998 and December 2005. Follow-up was by postal questionnaires at 3 and 6 months, 1, 2, 3 and 5 years. Intervention Bilateral LUNA or laparoscopy without pelvic denervation (no LUNA); participants blinded to the treatment allocation. Main outcome measures The primary outcome was pain, assessed by a visual analogue scale. Data concerning the 3 types of pain (non-cyclical, dysmenorrheal, and dyspareunia) were analyzed separately as was the worst pain level experienced from any of these 3 types of pain. Secondary outcomes were quality of life (EuroQoL EQ-5D and EQ-VAS).

After a median follow up of 69 months, there were no significant differences between the visual analogue pain scales for for the worst pain reported (mean difference between LUNA group and No LUNA group: -0·04cm, 95% confidence interval (CI), -0·33 to 0·25cm; p=0·80), non- cyclical pain (-0·11cm, 95%CI -0·50 to 0·29cm; p=0·60) dysmenorrhoea (-0·09cm, 95%CI -0·49 to 0·30cm; p=0·60), or dyspareunia (0·18cm, 95%CI -0·22 to 0·62cm; p=0·40). No differences were observed between the LUNA group and the no LUNA group for quality of life. Chapter 5 63

Among women with chronic pelvic pain, LUNA did not result in improvements in pain, dysmenor- rheal, dyspareunia or quality of life, compared to laparoscopy without pelvic denervation. Trial Registration Controlled-trials.com identifier ISRCTN number: 41196151

Chronic pelvic pain (CPP) in women is as common as asthma and chronic back pain in primary care1.2 CPP continues to be one of the most difficult and perplexing of women’s health problems with a multifactorial etiology.3 Chronic pelvic pain has a major impact on health-related quality of life, work attendance and productivity4 and health care utilization, accounting for 40% of referrals for diagnostic laparoscopy,5 and is an important contributor to health care expeditures.6 Treatmentsfor CPP are often unsatisfactory.7 As part fo the evaluation and management phase, patients often undergo diagnostic laparoscopy, 8 but actionable pathology is found only occa- sionally identified.9, 10 Negative findings at laparoscopy, and follow up with ultrasound, may pro- vide reassurance and relief to some patients, 11 but in the absence of underlying pathology no established gynaecological treatments are available. Nerve plexuses and parasympathetic ganglia in the uterosacral ligaments 12, 13 are thought to carry pain signals from the uterus, cervix, and other pelvic structures. Conventional open vagi- nal and abdominal procedures have been used to interrupt these nerve trunks by dividing the attachments of the uterosacral ligaments to the cervix in women with dysmenorrhoea. 14, 15 In part because these procedures are invasive and carry risk they have not been widely adopted. Laparoscopic uterosacral nerve ablation (LUNA) is performed after diagnostic laparoscopy and can be completed using lasers or electro-diathermy, and has become increasingly used. 16, 17 Systematic reviews of the current research evidence on LUNA’s efficacy are inconclusive.18, 19 and a National Institute of Clinical Excellence report suggested that there was not sufficient evidence of its value. 20 Clinicians’ beliefs about LUNA’s effectiveness vary widely21 and LUNA remains a controversial procedure. We conducted a single-blind, randomized controlled trial comparing LUNA with laparoscopy without pelvic denervation.

The LUNA Trial was a multicenter, prospective randomized intervention trial with patient-blinded, patient-rated assessment of outcomes to evaluate LUNA. 22, 23 Ethics committee approval was obtained from the West Midlands Multi-centre Research Ethics Committee (reference number LUNA: a randomised trial 64 99/7/03). Patients presenting to gynaecology outpatient clinics with CPP (dysmenorrhoea, non- cyclical pain or dyspareunia) of longer than 6-month duration located within between and below the anterior iliac crests, and who were undergoing diagnostic laparoscopy for differential diagno- sis of CPP , were invited to participate in our study. Women were ineligible if they had previous LUNA, hysterectomy or therapeutic procedures for, or diagnosis of, moderate to severe endometriosis or major pelvic inflammatory disease. Written consent was obtained before surgery. At laparoscopy, women were excluded if they were found to have more than minimal pathology (i.e. American Fertility Society endometriosis score >5 or significant adhesions or serious adnexal pathology) or if bilateral LUNA was technically unfea- sible. Intraoperatively, eligible patients were randomized by telephone call to the Birmingham University Clinical Trials Unit, or through its Internet based randomization service, to LUNA or no denervation. Randomization involved a computer minimization program to balance group allocations for site of pain, parity, self reported sexual activity status and presence or absence of minimal pathology. To avoid eligibility classification bias, treatment allocation was issued only after the surgeon had inspected the pelvis and ensured that the patient fulfilled all of the inclusion criteria and did not have any of the exclusion criteria. Those allocated to LUNA had the procedure performed immediately by the same laparoscopic surgeon, who had prior experience of the technique and who followed a common protocol. 24 In a typical case, after inspection of the posterior leaf of the broad ligament to identify ureters and any pelvic venous congestion, the ablation was performed as close to the posterior aspect of the cervix as possible and continued for a minimum of 1 cm posterolaterally on either side with the intended aim of destroying the sensory nerve fibres and the secondary ganglia as they left the uterus and lie within the uterosacral ligaments. Full or partial transaction of the ligaments was achieved bilaterally with laser or electro-diathermy, according to the surgeons’ preference. In centers where surgeons used 2 secondary ports to perform LUNA, a second 5 mm incision was made in the patients in the no LUNA group through the skin in an area corresponding to where an additional port site was made. This approach of sham incisions has been used in a previous trial 25 and was ethically justified to help avoid bias in the patient rated assessment of a subjective outcome like pain.26 All women were asked at least 12 months after randomization whether they believed they had LUNA or no LUNA. Baseline data were collected following consent and prior to laparoscopy. At 3 and 6 months following randomization, and at 1, 2, 3 and 5 years, the same questionnaires were mailed to Chapter 5 65 patients with a pre-paid return envelope. Non responders were followed up through postal and/ or telephone reminders or, if this failed, via their general practitioners. The primary outcome of pain was rated using a 10 cm visual analogue scale (VAS), 27 anchored at one end as no pain at all and the other as worst imaginable pain. The VAS ratings were obtained for each of the 3 types of pain: non-cyclical pain (pain at any other times, other than during periods or during intercourse), dysmenorrhoea (pain during your periods) and dyspareunia (pain during intercourse. Women rated the degree of pain by placing a mark on the line and scale values were obtained by measuring the distance from zero to that mark. This measurement is validated as a sensitive measure for large group comparisons.28 The secondary outcomes were health-related quality of life measured using a generic instrument (EuroQOL EQ-5D and EQ-VAS),29 and a proforma recording the need for additional treatments, resource usage, days off work and complications of surgery. The EQ-5D is measured on a 0-1 scale based on responses to five questions about life quality and the EQ-VAS is measured on a 0 - 100 scale. The sample size was powered to detect a small to medium effect of LUNA in alleviating pain symptoms compared to laparoscopy without pelvic denervation. To confirm or refute a 0·3 standard deviation effect size,30 equivalent to a difference between groups of 1.2cm on the visual analogue scale, at a two-sided α=0·05 and ß=0·2 (80% power), 175 women in each group (i.e. 350 in total) were required. Allowing for a 20% loss to follow-up, the recruitment target was inflated to 420. Considering that existing research in this condition has shown substantial rates of loss to follow-up, recruitment continued until the end of the funding period when 487 women were included. An independent data monitoring committee reviewed confidential interim analy- ses annually and, recommended at each meeting continuing recruitment because the data were inconclusive. All participants were analyzed in the group to which they were allocated, using all available data, and SAS statistical software version 9 (SAS Institute, Cary, North Carolina). Baseline character - istics of the patients enrolled in the two groups were compared to ensure that randomization has produced comparable groups. Data for the various outcome measures were presented as means and mean differences over time, with 95% confidence intervals (CIs). For the primary outcome, we analyzed data separately concerning the three types of pain (non- cyclical pain, dysmenorrhoea, and dyspareunia) and performed an analysis of the worst pain level experienced from any of the three types of pain. Comparisons between groups over time were undertaken using repeated measures analyses, 31 a statistically efficient approach that includes all LUNA: a randomised trial 66 of the follow up data collated during the study, increasing power over analysis of data at individual timepoints. Pain scores at 12 months were compared using standard two sample t-tests. The principal analysis for the worst pain experienced from any of the three types of pain was an intention to treat analysis using multiple imputation. 32,33 To investigate the impact of missing data, the analyses of the individual types of pain at 12 months were repeated using the last observa- tion carried forward method of imputation. All comparisons were two-sided and were considered statistically significant if p<0.05. Sub group analyses were chosen on the basis of anticipated variations in pain and potential benefit from LUNA, but were considered hypothesis generating. Pre-specified sub-groups were those used to stratify the randomization, namely site of pain (central, not central) and presence or absence of some minimal pathology for all types of pain, parity (nulliparous, multiparous) and whether women were sexually active or not.

Between February 1998 and December 2005, 487 women were randomized into the LUNA trial from 18 centers. A further 105 were consented but were found at laparoscopy to have pathol- ogy that made them ineligible for randomization, or anatomy that precluded LUNA from being performed. No women in the control group received LUNA, whereas five women allocated LUNA ultimately did not have LUNA performed bilaterally due to technical difficulties, but were analyzed in the LUNA group. Figure 1 shows the trial profile. Baseline pain data were missing on 26 (5%) participants, including 10 participants from one centre where a batch of baseline data was lost. Baseline characteristics of the women did not differ between the two groups (Table 1) and there were not any differences in cointerventions between the groups. Blinding was maintained, apart from 13 women who asked to be informed of their allocation, although in a sub-sample of 211 who had been blinded to their allocation, 122 correctly guessed their allocation (58%) . The majority of women had multiple types of pain. A total of 168 participants reporting non- cyclical pain dysmenorrhoea, and dyspareunia (36%). and 113 reporting dysmenorrhoea and dyspareunia (24%). In 266 (54%) women, there was no obvious pathology identified, suggestive of primary dysmenorrhoea. A further 146 had minimal to mild endometriosis (30%), 86 had adhe- sions (18%), 13 had pelvic inflammatory disease (3%), and 35 had other visible pathologies (7%), the majority being subserosal fibroids and small ovarian cysts. Chapter 5 67 Figure 1: Selection of participants for the Laparoscopic Uterosacral Nerve Ablation (LUNA) Trial a Twenty-six patients had more than 1 reason for exclusion. b Indicates worst pain level experienced from any of the 3 types of pain analyzed (noncyclical pain, dysmenorrhea, and dyspareunia). Median time in the study was 69 months with 72% of participants having reached 5 years of follow-up. The differences in pain are shown in Figure 2. The results are presented as the mean pain scores from the VAS for each randomized group in the upper graph, and as the difference between the two groups in the lower graph, where a positive value indicates better pain relief with LUNA than without LUNA. There was no difference reported for the worst pain level experienced from any of the 3 types of pain (mean difference between the LUNA group vs the no LUNA group, −0.02 cm, 95% CI −0.61 to 0.65 cm; p=0.90 at 12 months; −0.04 cm, 95% CI, −0.33 to 0.25 cm; p =0.80 over all time points), noncyclical pain (0.17 cm, [95% CI −0.40 to 0.74 cm; p =.50 at 12 months; −0.11 cm, 95% CI, −0.50 to 0.29 cm; p =0.60 over all time points), dysmenorrhea (−0.10 cm, 95% CI −0.70 to 0.50 cm; p =0.70 at 12 months; −0.09 cm, 95% CI −0.49 to 0.30 cm; p =0.60 over all time points), or dyspareunia (0.34 cm, 95% CI −0.34 to 1.02 cm; p =0.30 at 12 months; 0.18 cm, 95% CI −0.22 to 0.62 cm; p =0.40 over all time points). LUNA: a randomised trial assurance and relief to some patients11 but in the absence of underlying pa- thology, no established gynecological treatments are available. Nerve plexuses and parasympa- thetic ganglia in the uterosacral liga- ments12,13 are thought to carry pain sig- nals from the uterus, cervix, and other pelvic structures. Conventional open vaginaland abdominalprocedureshave been used to interrupt these nerve trunks by dividing the attachments of the uterosacral ligaments to the cervix in women with dysmenorrhea.14,15 In part because these procedures are in- vasive and carry risk and their efficacy has not been established, they have not been widely adopted. Laparoscopic uterosacral nerve ablation (LUNA) is performed after diagnostic laparos- copy and can be completed using la- sers or electrodiathermy and has be- come increasingly used.16,17 Systematic reviews of the current research evi- dence on LUNA’s efficacy are incon- clusive.18,19 A NationalInstituteof Clini- cal Excellence report suggested that there was not sufficient evidence of its value. 20 Clinicians’ beliefs about LUNA’s effectiveness vary widely21 and LUNA remainsacontroversial proce- dure.We conductedasingle-blind, ran- domized controlled trial comparing LUNA with laparoscopy without pel- vic denervation.

The LUNA trial wasamulticenter, pro- spective, randomized intervention trial with patient-blinded, patient-rated as- sessment of outcomes to evaluate LUNA. 22,23 Ethics committee approval was obtained from the West Midlands Multicenter Research Ethics Commit- tee (reference No. 99/7/03). Patients presenting to gynecology outpatient clinics with chronic pelvic pain (non- cyclical pain, dysmenorrhea, or dyspa- reunia) lasting longer than 6 months, located within and below the anterior iliac crests, and who were undergoing diagnostic laparoscopy for differential diagnosis of chronic pelvic pain were invited to participate in our study. Women were ineligible if they had previousLUNA,hysterectomy,or thera- peutic procedures for, or diagnosis of, moderate to severe endometriosis or major pelvic in/f_lammatory disease. Written informed consent was ob- tained before surgery. At laparoscopy, women were excluded if they were found to have more than minimal pa- thology (ie, American Fertility Society endometriosis score 5 or signi/f_icant adhesions or serious adnexal pathol- ogy) or if bilateral LUNA was techni- cally unfeasible. Intraoperatively, eli- gible patients were randomized via a telephone call to the Birmingham Uni- versity Clinical Trials Unit, or through its Internet-based randomization ser- vice, to the LUNA group or the no LUNA group. Randomization involvedacom- puter minimization program to bal- ance group allocations for site of pain, parity, self-reported sexual activity sta- tus, and presence or absence of mini- mal pathology.To avoid eligibilityclas- si/f_icationbias, treatmentallocationwas issued only after the surgeon had in- spected the pelvis and ensured that the patient ful/f_illedall of the inclusion cri- teria and did not have any of the ex- clusion criteria. Those allocated to the LUNA group had the procedure performed immedi- ately by the same laparoscopic sur- geon who had prior experience of the technique and who followedacom- mon protocol.24 Inatypical case, after inspection of the posterior leaf of the broad ligament to identify ureters and any pelvic venous congestion, the ab- lation was performed as close to the posterior aspect of the cervix as pos- sible and continued foraminimum of 1 cm posterolaterally on eithersidewith the intended aim of destroying the sen- sorynerve/f_ibersand the secondarygan- glia as they left the uterus and lie within the uterosacral ligaments. Full or partial transactionof the liga- ments was achieved bilaterally with la- ser or electrodiathermy, according to the surgeons’ preference. In centers in which surgeons used2additional ports to perform LUNA,asecond 5-mm in- Figure 1. Selection of Participants for the Laparoscopic Uterosacral Nerve Ablation (LUNA) Trial Primary pain analyses at 12 mo 187 Included in worst pain level analysisb 185 Included in noncyclical pain analysis 167 Included in dysmenorrhea analysis 142 Included in dyspareunia analysis Primary pain analyses at 12 mo 192 Included in worst pain level analysisb 185 Included in noncyclical pain analysis 170 Included in dysmenorrhea analysis 138 Included in dyspareunia analysis 5 Withdrew consent prior to 12-mo follow-up 51 Missing pain data at 12-mo follow-up 4 Withdrew consent prior to 12-mo follow-up 48 Missing pain data at 12-mo follow-up 243 Randomized to receive LUNA 229 Received LUNA as assigned 5 Did not receive LUNA due to technical difficulties 9 Not known whether LUNA was received 244 Randomized to receive laparoscopy without pelvic denervation (no LUNA) 231 Did not receive LUNA as assigned 13 Not known whether LUNA was received 487 Randomized 592 Patients assessed for eligibility and provided consent prior to diagnostic laparoscopy 105 Excludeda 63 Moderate or severe endometriosis 51 LUNA technically not feasible 26 Moderate or severe adhesions 3 Other pathology considered significant 6 Moderate or severe pelvic inflammatory disease a Twenty-six patients had more than1reason for exclusion. bIndicates worst pain level experienced from any of the3types of pain analyzed (noncyclical pain, dysmen- orrhea, and dyspareunia). LAPAROSCOPIC UTEROSACRAL NERVE ABLATION FOR CHRONIC PELVIC PAIN 956 JAMA, September 2, 2009—Vol 302, No. 9 (Reprinted) ©2009 American Medical Association. All rights reserved. at University of Birmingham on October 12, 2009 www.jama.comDownloaded from 68 22 Table 1 Baseline characteristics of participants in the Laparoscopic Uterosacral Nerve Ablation (LUNA) trial LUNA n (%); total=243 No LUNA n (%); total=244 Age1 30·6 (7·53; 17-64) 30·5 (7·48; 17-57) Clinical presentation Nulliparous 87 (36) 92 (38) Sexually active 195 (80) 193 (79) Type of pain Dysmenorrhoea 184 (76) 179 (73) Dyspareunia 2 158 (65) 149 (61) Non-cyclical pain 159 (65) 153 (63) All three types of pain 89 (37) 79 (32) Location of pain Central 168 (69) 167 (68) Laparoscopic findings Any visible pathology 110 (45) 111 (45) Adhesions 49 (20) 37 (15) Pelvic inflammatory disease 4 (2) 9 (4) Endometriosis None 177 (73) 164 (67) Minimal 41 (17) 52 (21) Minimal, ablated 25 (10) 28 (11) Pain medication Painkillers3 155 (64) 156 (64) Anti-depressants4 16 (7) 28 (11) Hormonal contraceptives Combined oral contraceptive 33 (14) 33 (13) Mini-pill 4 (2) 5 (2) Mirena coil 1 (<1) 0 (0) Contraception (not specified) 30 (12) 24 (10) Indication for other medication Irritable bowel syndrome 2 (1) 1 (0) Bladder pain 0 (0) 1 (0) Urinary tract infection 2 (1) 1 (0) Migraine 5 (2) 2 (1) Asthma 19 (8) 15 (6) Blood pressure 4 (2) 4 (2) 1 Mean (standard deviation; range) 2 % of sexually active women only 3 13 and 8 missing data items for LUNA and no LUNA respectively 4 20 and 20 missing data items Table 1: Baseline characteristics of participants in the Laparoscopic Uterosacral Nerve Ablation (LUNA) trial Chapter 5 69 Using last observation carried forward for imputation of missing observations at 12 months, we found no significant difference between the LUNA group and the no LUNA group for non- cyclical pain (0.35cm, 95% CI -0.19 to 0.88cm; p=0.2), dysmenorrhea (-0.16cm, 95% CI -0.73 to 0.40cm; p=0.6), or dyspareunia (0.26cm, 95%CI -0.39 to 0.92cm; p=0.4). A similar lack of efficacy was observed for the outcome measures concerning health-related quality of life with the mean difference in the EQ-5D being 0.03 (95% CI -0.03 to 0.09; p=0.3) and that in EQ-VAS being -0.78cm (95% CI, -3.9 to 5.4; p=0.3) at 12 months. Between 9 and 12 months, no differences were found between the LUNA group and the no LUNA group in terms of days off work (27% vs 22%, respectively, took at least 1 day off work; p=0.20) or in the number of general practitioner surgery visits (mean [SD] number of visits, 1.9 [1.1] vs 2.5 [2.0], respectively; p=0.08). The pre- specified subgroup analyses using repeated- measures analysis appears in Table 2. There were 8 cases of minor haemorrhaging while performing the LUNA procedure and one case that converted to an open procedure. One participant not allocated LUNA suffered ureteric damage. Comment The LUNA trial was designed to assess the effects of LUNA, compared to no denervation, among women undergoing diagnostic laparoscopy for chronic pelvic pain. LUNA did not alleviate pain - non-cyclical pain, dysmenorrhoea, or dyspareunia - or improve life quality, irrespective of the pres- ence or absence of mild endometriosis. A Cochrane review19 did suggest a subgroup benefit for patients with dysmenorrhoea that our study did not find. This finding came from two small studies34, 35 totaling 68 randomised participants, one of which34 did not have strictly concealed randomization. 23 Table 2 Pre-specified sub-group analyses using repeated measures analysis Worst pain Dysmenorrhea Dyspareunia Non-cyclical pain Subgroup Treatment effect (95% CI) p value Treatment effect (95% CI) p value Treatment effect (95% CI) p value Treatment effect (95% CI) p valu e Nulliparous 0.34 (-0.06-0.74) 0.14 (-0.28-0.54) 0.44 (-0.04-0.92) -0.02 (-0.41-0.37) Parous -0.08 (-0.41-0.24) 0.5 -0.20 (-0.55-0.15) 0.4 -0.32 (-0.68-0.05) 0.1 -0.13 (-0.47-0.20) 0.6 No pathology 0.10 (-0.16-0.36) -0.11 (-0.39-0.17) 0.08 (-0.22-0.39) -0.08 (-0.34-0.18) Any minimal pathology 0.19 (-0.81-1.18) 0.2 0.64 (-0.29-1.56) 0.3 -0.54 (-1.04-0.12) 0.02 0.64 (-0.68-1.39) 0.2 Mild/minimal endometriosis 0 .2 (-0.59-0.62) 0.8 Central pain -0.03 (0.31-0.30) -0.15 (-0.46-0.16) -0.06 (-0.41-0.30) -0.15 (-0.46-0.16) No central pain 0.10 (-0.49-0.49) 0.2 -0.19 (-0.74-0.36) 0.2 0.21 (-0.33-0.76) 0.1 0.01 (-0.5-0.51) 0.3 Table 2: Pre-specified sub-group analyses using repeated measures analysis LUNA: a randomised trial 70 For the primary outcome, we ana- lyzed data separately concerning the 3 types of pain (noncyclical pain, dysmen- orrhea, and dyspareunia) and per- formed an analysis of the worst pain level experienced from any of these 3 types of pain. Comparisons between groups over time were undertaken using repeated- measures analyses, 31 a statistically effi- cient approach that includes all of the fol- low-up data collated during the study, increasing power over analysis of data at individual time points. Pain scores at 12 months were compared using standard 2-sample t tests. The principal analysis for the worst pain level experienced from any of the 3 types of pain was an intention-to- treat analysis using multiple imputa- tion. 31-33 To investigate the effect of miss- ing data, the analyses of the individual types of pain at 12 months were re- peated using the last observation car- ried forward method of imputation. All comparisons were 2-sided and were con- sidered statistically significant ifP/H11021.05. Subgroup analyses were chosen on the basis of anticipated variations in pain and potential benefit from LUNA, but were considered hypothesis generating. Pre- specified subgroups were those used to stratify the randomization, namely site of pain (central, not central), presence or absence of minimal pathology for all types of pain, parity (nulliparous, mul- tiparous), and whether women were sexually active or not.

Between February 1998 and Decem- ber 2005, 487 women were random- ized into the LUNA trial from 18 UK hospitals. A further 105 patients pro- vided consent but were found at lapa- roscopy to have pathology that made them ineligible for randomization, or anatomy that precluded LUNA from being performed. No women in the con- trol (no LUNA) group received LUNA, whereas 5 women in the LUNA group ultimately did not have LUNA per- formed bilaterally due to technical dif- ficulties, but were analyzed in the LUNA group. F IGURE 1 shows the trial profile. Baseline pain data were miss- Figure 2. Effect of Laparoscopic Uterosacral Nerve Ablation (LUNA) at 12 Months and at Each Time Point Noncyclical painB No. of observations LUNA No LUNA 219 228 181 189 185 185 157 165 159 147 104 96 219 228 181 189 185 185 157 165 159 147 104 96 10 8 4 6 2 0 Mean VAS Pain Score, cm 0 3 6 12 24 36 48 60 Time, mo 0 3 6 12 24 36 48 60 Time, mo 4 2 0 –2 –4 Difference in Mean VAS Pain Score, cm No. of observations LUNA No LUNA 228 234 186 195 192 187 158 168 161 151 106 97 LUNA No LUNA 10 8 4 6 2 0 Mean VAS Pain Score, cm Worst pain levelaA 0 3 6 12 24 36 48 60 Time, mo 0 3 6 12 24 36 48 60 Time, mo 4 2 0 –2 –4 Difference in Mean VAS Pain Score, cm No. of observations LUNA No LUNA 177 183 137 146 138 142 121 119 112 112 68 72 177 183 137 146 138 142 121 119 112 112 68 72 10 8 4 6 2 0 Mean VAS Pain Score, cm DyspareuniaD 0 3 6 12 24 36 48 60 Time, mo 0 3 6 12 24 36 48 60 Time, mo 4 2 0 –2 –4 Difference in Mean VAS Pain Score, cm No. of observations LUNA No LUNA 216 228 166 180 170 167 143 144 137 124 91 74 216 228 166 180 170 167 143 144 137 124 91 74 10 8 4 6 2 0 Mean VAS Pain Score, cm DysmenorrheaC 0 3 6 12 24 36 48 60 Time, mo 4 2 0 –2 –4 0 3 6 12 24 36 48 60 Time, mo Difference in Mean VAS Pain Score, cm 228 234 186 195 192 187 158 168 161 151 106 97 The graph on the right in each lettered part of the figure shows the difference in mean visual analogue scale (VAS) pain scores and 95% confidence intervals; values greater than 0 indicate that LUNA is a better therapy than no LUNA. The error bars indicate 95% confidence intervals. a Indicates worst pain level experienced from any of the 3 types of pain analyzed (noncyclical pain, dysmen- orrhea, and dyspareunia). LAPAROSCOPIC UTEROSACRAL NERVE ABLATION FOR CHRONIC PELVIC PAIN 958 JAMA, September 2, 2009—Vol 302, No. 9 (Reprinted) ©2009 American Medical Association. All rights reserved. at University of Birmingham on October 12, 2009 www.jama.comDownloaded from Figure 2: Effect of Laparoscopic Uterosacral Nerve Ablation (LUNA) at 12 Months and at Each Time Point Chapter 5 71 The LUNA trial is 4 times larger than any previously published trial evaluating neuroablation in chronic pelvic pain. It may be more reliable than any previous study of LUNA and was also designed to minimize bias, with concealment of allocation before randomization and blinded outcome assessment. Women were not told whether they received LUNA or not. Although the majority were not informed of their allocation, there is a suggestion that a small proportion were able to guess correctly. If anything, however, this would be likely to enhance the apparent value of LUNA. LUNA was adopted by many practitioners because afferent nerves from pelvic organs passed through the uterosacral ligament and it was believed that disruption of these would reduce the perceived pain. Lack of efficacy in this study, and in prior studies, provide evidence that the ana- tomical and physiological picture of chronic pelvic pain is more complicated. Anatomically, there are at least five pathways that transmit signals from noxious stimuli in the pelvis. These nerve trunks vary in location and can intersect, with the potential for neuronal cross-talk. LUNA may obliterate some of the nerve fibers, but others are interwoven with the pelvic arteries and ureters. Aggressive ablation more laterally risks damaging the ureter, so most procedures are compro- mised in their ability to achieve complete neurodestruction. Furthermore, it is conceivable that nerves regenerate, or there may be a retrograde rerouting of nerve pathways. We followed participants for longer than 6 months because laparoscopy may have a placebo effect for up to 3-6 months. 36, 37 We found no benefit for LUNA at any time point, but found im- provement in pain at 3 months in both the LUNA group and the No LUNA group. This early pain reduction may be a placebo effect; attributable to the reassurance provided by the laparoscopy that there was no serious pathology. A comparison of diagnostic laparoscopy against no laparo- scopic investigation would be required to establish benefit. Alternatively, it could be a regression to the mean effect, with women more likely to undergo laparoscopic investigation when their pain is at its worst, rather than average level. This study has several limitations. We did not obtain follow-up data on all women but drop out rates were similar in each group and multiple imputation and last observation carried forward analyses produced near identical findings to those of the observed data. Given that we observed no effect of LUNA, the question arises whether this might be due to type II error (i.e. inadequate statistical power). A clinically significant difference in pain has been defined as 2 points on a 10-point (cm) VAS for chronic pelvic pain 36, 38 and also for other types of pain 39 whereas our trial had the power to detect a 1.2 point difference at 12 months and even smaller differences over LUNA: a randomised trial 72 time. In every comparison, the confidence intervals around the mean difference in VAS scores between the groups were less than ±1.2 points. Taking worst pain experienced at 12 months as an example, the pain score was 0.02cm lower in the LUNA group than no LUNA group and the 95% confidence interval was 0.61cm lower to 0.65cm higher (i.e. well below the clinically significant improvement). In conclusion, among women with chronic pelvic pain, LUNA did not result in improvements in pain, dysmenorrheal, pelvic pain or quality of life, compared to laparoscopy without pelvic den- ervation. Chapter 5 73

(1) Zondervan KT, Yudkin PL, Vessey MP , Dawes MG, Barlow DH, Kennedy SH. Prevalence and incidence of chronic pelvic pain in primary care: evidence from a national general practice database. BJOG 1999;106(11):1149-55. (2) Latthe P , Latthe M, Say L, Gulmezoglu M, Khan KS. WHO systematic review of prev- alence of chronic pelvic pain: a neglected reproductive health morbidity. BMC Public Health 2006;6(1):177. (3) Latthe P ., Mignini L, Gray R, Hills R, Khan K. Factors predisposing women to chronic pelvic pain: systematic review. BMJ 2006;332(7544):749-51. (4) Sundell G, Milsom I, Andersch B. Factors influencing the prevalence and severity of dys- menorrhoea in young women. BJOG 1990;97(7):588-94. (5) Howard FM. The role of laparoscopy in chronic pelvic pain: promise and pitfalls. Obstet Gynecol Surv 1993;48(6):357-87. (6) Winkel CA. Modeling of medical and surgical treatment costs of chronic pelvic pain: New paradigms for making clinical decisions. Managed Care 1999;5(5):S276-S290. (7) Mathias SD, Kuppermann M, Liberman RF, Lipschutz RC, Steege JF. Chronic pelvic pain: prevalence, health-related quality of life, and economic correlates. Obstet Gynecol 1996;87(3):321-7. (8) RCOG Guidelines and Audit Committee. The initial management of chronic pelvic pain. Royal College of Obstetricians and Gynaecologists; 2005. Report No.: Guideline 41. (9) Howard FM. The role of laparoscopy as a diagnostic tool in chronic pelvic pain. Best Practice & Research Clinical Obstetrics & Gynaecology 2000;14(3):467-94. (10) Porpora MG, Gomel V. The role of laparoscopy in the management of pelvic pain in women of reproductive age. Fertil Steril 1997;68(5):765-79. (11) Ghaly AFF. The psychological and physical benefits of pelvic ultrasonography in patients with chronic pelvic pain and negative laparoscopy. A random allocation trial. J Obstet Gynaecol 1994;14:269-71. (12) Campbell RM. Anatomy and physiology of sacrouterine ligaments. Am J Obstet Gynecol 1950;59:1. (13) Latarjet A, Roget P . Le plexus hypogastrique chez la femme. Gynecol Obstet (Paris) 1922;6:225. (14) Doyle JB. Paracervical uterine denervation by transection of the cervical plexus for the relief of dysmenorrhoea. Am J Obstet Gynecol 1955;70:1. (15) Doyle JB, Des Rosiers JJ. Paracervical uterine denervation for the relief of pelvic pain. Clinical Obstet Gynecol 1963;6:742-53. (16) Latthe P , Powell R, Daniels J et al. Variation in practice of Laparoscopic uterosacral nerve ablation: A European survey. J Obstet Gynaecol 2004;24(5):547-51. LUNA: a randomised trial 74 (17) Daniels J, Gray R, Khan K, Gupta J. Laparoscopic uterine nerve ablation: A survey of gynaecological practice in the UK. Gynaecol Endosc 2000;9(3):157-9. (18) Khan KS, Khan SF, Nwosu CR, Dwarakanath LS, Chien PFW. Laparoscopic uterosacral nerve ablation in chronic pelvic pain: An overview. Gynaecol Endosc 1999;8(5):257-65. (19) Proctor ML, Latthe PM, Farquahr CM, Khan KS, Johnson NP . Surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2005;4. (20) National Institute for Health and Clinical Excellence. Interventional Procedure Guidance 234. London, England. National Institute for Health and Clinical Excellence; 2007 (21) Latthe PM, Braunholtz DA, Hills RK, Khan KS, Lilford R. Measurement of beliefs about effectiveness of laparoscopic uterosacral nerve ablation. BJOG 2005;112(2):243-6. (22) Latthe P ., Khan KS, Gupta JK et al. A randomised controlled trial to assess the efficacy of Laparoscopic Uterosacral Nerve Ablation (LUNA) in the treatment of chronic pelvic pain: The trial protocol. Biomed Central Women’s Health 2003 8;3. (23) University of Birmingham Clinical Trials Unit. The LUNA Trial. http://www luna bham ac uk 2003. (24) Sutton C, Whitelaw N. Laparoscopic uterosacral nerve ablation for intractable dysmenor- rhoea. In: Sutton C, editor. Endoscopic surgery for gynaecologists.London: WB Saun- ders; 1993. p. 159-63. (25) Sutton CJ, Ewen SP , Whitelaw N, Haines P . Prospective, randomized, double-blind, con- trolled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertil Steril 1994;62(4):696-700. (26) Johnson AG, Dixon JM. Removing bias in surgical trials. BMJ 1997;314(7085):916-7. (27) Revill SI, Robinson JO, Rosen M, Hogg MI. The reliability of a linear analogue for evaluat- ing pain. Anaesthesia 1976;31(9):1191-8. (28) Jensen MP , Turner JA, Romano JM, Fisher LD. Comparative reliability and validity of chronic pain intensity measures. Pain 1999;83(2):157-62. (29) Kind P . The EuroQol instrument: An index of health-related quality of life. In: Spliker B, editor. Quality of life and PharmacoEconomics in clinical trials. 2nd. ed. Philadelphia: Lip- pincott-Raven; 1996. (30) Cohen J. Statistical power analysis for the behavioural sciences. Revised ed. New York: Academic Press; 1977. (31) Goldstein H. Multilevel statistical models. 3rd ed. London: Arnold Publishers; 2003. (32) Rubin.D.B. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley and Sons, Inc; 1987. (33) Schafer JL. Analysis of Incomplete Multivariate Data. New York: Chapman and Hall; 1997. (34) Lichten EM, Bombard J. Surgical treatment of primary dysmenorrhea with laparoscopic uterine nerve ablation. J Reprod Med 1987;32(1):37-41. Chapter 5 75 (35) Johnson NP , Farquhar CM, Crossley S et al. A double-blind randomised controlled trial of laparoscopic uterine nerve ablation (LUNA) for women with chronic pelvic pain. BJOG 2004;111(9):950-9. (36) Baker PN, Symonds EM. The resolution of chronic pelvic pain after normal laparoscopy findings. Am J Obstet Gynecol 1992;166(3):835-6. (37) Swank DJ, Swank-Bordewijk SC, Hop WC et al. Laparoscopic adhesiolysis in patients with chronic abdominal pain: a blinded randomised controlled multi-centre trial. Lancet 2003;361(9365):1247-51. (38) Zullo F, Pellicano M, DeStefano R. Efficacy of Laparoscopic Pelvic Denervation in Central- type Chronic Pelvic Pain: A multicentre study. J Gynecol Surg 1996;12:35-40. (39) Biljsma JW. Patient centred outcomes in arthritis. Ann Rheum Dis 2007;64:1-2. LUNA: a randomised trial 76 77 Chapter 6 Meta-analysis using individual patient data from randomised trials to assess the effectiveness of laparoscopic uterosacral nerve ablation in the treatment of chronic pelvic pain: a proposed protocol 78 Chapter 6

Background: Currently, there are a number of clinical trials, but no international collaboration for collating research on effectiveness of laparoscopic uterosacral nerve ablation (LUNA) for al- leviating chronic pelvic pain.

Meta-analysis was used by collecting individual patient data (IPD) from the existing trials, to provide a comprehensive assessment of the effectiveness of LUNA that will be generalis- able in various clinical contexts.

IPD will be sought and collected from all relevant (both already finished and continu- ing) randomised trials identified through previous systematic reviews. After obtaining raw data and cleaning the database, analysis will be of all patients ever randomised based on the inten- tion-to-treat principle using endpoints measured at 12 months following randomisation. Proposal: We will update searches, contact all authors, obtain data in whatever form it can be provided, build a single database, produce results for individual studies, have them verified by original authors, explore of any heterogeneity and reasons behind it and finally pool all raw data in to a meta-analysis using appropriate statistical methods. The project will test the effectiveness of LUNA for women with chronic pelvic pain. It will also motivate collaborating primary investigators to undertake new primary studies to corroborate or improve upon the conclusions derived from the retrospective analysis.

Chronic pelvic pain is a common condition with a major impact on health-related quality of life, work productivity and health care utilisation, 1-3 costing an estimated £158 million per year to the NHS.4 An effective treatment for this condition has evaded the medical profession for centuries. Even today only 20-25% patients respond to conservative management.5 When such treatment fails, a diagnostic laparoscopy is performed.1;3;6 The cause of the pain is not always obvious as no pathology is seen in 40-60% of the cases. 1 In the absence of pathology there is no established treatment. The Lee-Frankenhauser sensory nerve plexuses and parasympathetic ganglia in the uterosacral ligaments carry pain from the uterus, cervix and other pelvic structures. 7-10 Interrup- tion of these nerve trunks by laparoscopic uterosacral nerve ablation (LUNA) may alleviate pain.11 However, the balance of benefits and risks of this intervention have not been reliably assessed. Chapter 6 79 LUNA has, nevertheless, been introduced into practice, although there remains controversy re- garding indications for LUNA. We carried out a comprehensive systematic review of observational and randomised evidence on the efficacy of LUNA in the treatment of chronic pelvic pain. 11 For the treatment of primary dysmenorrhoea there was some evidence of the effectiveness of LUNA when compared to a control or no treatment. The comparison between LUNA and laparoscopic presacral neurec- tomy (LPSN) for primary dysmenorrhoea showed no significant difference in pain relief in the short term; however, long-term LPSN was shown to be significantly more effective than LUNA. For the treatment of secondary dysmenorrhoea six identified randomised controlled trials (RCT) s addressed endometriosis and one included women with uterine myomas. The treatment of LUNA combined with surgical treatment of endometrial implants versus surgical treatment of endometriosis alone showed that the addition of LUNA did not aid pain relief. For presacral neu- rectomy (PSN) combined with endometriosis treatment versus endometriosis treatment alone there was an overall difference in pain relief, although the data suggests this may be specific to laparoscopy and for midline abdominal pain only. Adverse events were significantly more com- mon for presacral neurectomy; however, the majority were complications such as constipation, which may spontaneously improve. This systematic review concluded that there is insufficient evidence to recommend the use of nerve interruption in the management of dysmenorrhoea, regardless of cause. 11 Hence, there is an urgent need for a methodologically sound and sufficiently powered analytic re- search to be undertaken, to confirm, or refute, any worthwhile effectiveness. A more realistic and unbiased assessment for the effectiveness of LUNA might be obtained via multivariable analyses that incorporate the clinical context in which investigations are carried out. Systematic reviews and conventional meta-analyses of such data increase the number of outcome events but do not permit the clinical context to be taken into account. Meta-analysis using individual patient data (IPD) from primary studies has the potential to esti- mate informativeness of the investigations in context, which has been introduced as the gold standard analytic approach in reviews of randomised controlled trials, 12-14 however no such anal- yses appear to exist in the current literature. This project will undertake IPD meta-analysis includ- ing all relevant studies identified in previously published systematic reviews. 15-21 In this way it will provide the most comprehensive and reliable means of assessing the effectiveness of LUNA in a clinical setting considering various clinical context. We aim to answer the following purposes through this IPD meta-analysis. Firstly, to test the hy- pothesis that in women with chronic pelvic pain in whom diagnostic laparoscopy reveals either no pathology or stage I-II endometriosis LUNA alleviates pain and improves life quality at 12 LUNA IPD Meta-analysis protocol 80 months, using raw data collated from studies included in systematic review. Secondly, to test the hypothesis that response to LUNA differs according to the site and cause of the pain by two secondary analyses – women with central pain and women with no visible pathology. Thirdly, to motivate collaborating primary investigators to undertake new, mutually planned, primary studies to corroborate or improve upon the conclusions derived from the retrospective analysis above, e.g. long term follow-up of randomised trials. Lastly, to initiate and advocate the execution of IPD meta-analysis in clinical research and to motivate others to experiment with it in other fields of medicine – if it were proven to be of value.

Identification Of Randomised Trials And Investigators Individual patient (raw) data will be sought from all currently existent and relevant studies of randomised trials identified in the previously published systematic review, including both already finished and continuing trials. All authors of included studies of randomised trials were invited formally or personally by the initiator of this study for collaboration in the spring of 2006 (a related website has been devel- oped). An e-mail system based team building exercise will be undertaken by bringing authors’ viewpoints together to an electronic forum. This forum will: examine the protocol for refinements; discuss the variables on which the data are to be collected, the data checking procedures and the main analyses to be performed; and agree on a timetable and a publication policy (a collabo- rative/group authorship will be proposed). Data Collection And Administration The Birmingham Clinical Trials Unit (BCTU) will act as the group’s secretariat and will hold the main database (International LUNA IPD Meta-analysis Collaborative Group, Birmingham, United Kingdom. Email [email protected], website: birmingham.ac.uk/bctu). All data, updates and cor- rections should be sent to BCTU in whatever format is most convenient for each group and will be stored in an Access database. All data will be held securely and treated in the strictest con- fidence. The data will not be used in any publication without the permission of the responsible trialists. Additional items may be collected if they are of interest to the Group and are available. In addition, we invite the principal investigators of included studies to send us their study protocol and details about study execution. We expect that many of these protocols will give us details that cannot be taken from the publications. Furthermore, the current project will ensure checks on consistency and ranges of the data. The original investigators will be contacted to supply missing data or to check values of doubtful validity. Chapter 6 81 Statistical Analysis Plan Analysis will be of all patients ever randomised and will be based on the intention to treat princi- ple. Visual analogue scale scores [on the scale 0 (no pain) to 10 (worst pain)] within the first 12 months of treatment will be combined and considered in a repeated measures analysis, giving us the advantage of being able to estimate overall effects over time utilising all available information. Multilevel modelling techniques in SAS PROC MIXED will be used, adjusting for baseline score and allowing for treatment type and study of origin using fixed or random effects as deemed appropriate. Confidence intervals for overall treatment effects will then be estimated from the model. Pre-specified subgroup analyses will be performed by: 1. Presence or absence of some coexisting pathology (endometriosis ± ablation; adhesions requiring adhesiolysis only; minimal pelvic inflammatory disease) 2. Site of pain (presence of central pain or not) 3. Age group 4. Parity (presence/ absence of children) We will also perform stratified analysis at study level depending on the control arm – diagnostic laparoscopy versus other intervention. By collecting IPD, investigation of heterogeneity between these subgroups and estimation of possible difference between will be possible, which is a clear advantage over using summary data from published reports. Furthermore, the collection of updated data, with longer follow up than in many of the individual trial reports, will enable reliable evaluation of treatment effects over time. Future Publications The results of the IPD meta-analysis will be presented and discussed at a meeting of the col- laborating trialists. Any subsequent report of the meta-analysis results will be published in the name of the collaborative group – the International LUNA IPD Meta-analysis Collaborative Group – and will be circulated to the collaborators for comment, amendment and approval before sub- mission. In case of any disagreement, the fundamental principle that will be applied is that the report should provide the meta-analysis results, presenting the totality of the available evidence, but will not include any interpretations of the data, except for those that are unanimously agreed by all collaborators. Any group will be free to withdraw its data from the collaboration at any time. LUNA IPD Meta-analysis protocol 82

This proposed international collaboration will provide tghe opportunity to achieve a new meth- odology of IPD meta-analysis in a field requiring urgent high quality research. It will also facilitate international collaboration in medical research while allowing individual investigators to maintain autonomy. The proposed analyses also provide the potential to provide high-level evidence on

of pain management in a timely manner. Chapter 6 83

(1) Howard FM. The role of laparoscopy in chronic pelvic pain: promise and pitfalls. Obstet Gynecol Surv. 1993;48:357-87. (2) Morris M,.O’Niell D. Out patient Gynaecology. BMJ 1958;2:1038. (3) Stones RW. Chronic pelvic pain. Personal Assessment in Continuing Education. London: Royal College of Obstetricians and Gynaecologists, 1997. (4) Davies L, Ganger K, Drummond M, Saunders D, Beard R. The economic burden of in- tractable gynaecological pain. J Obstet Gynecol 1992;12:46-54. (5) Henzl MR. Dysmenorrhoea; achievements and challenge. Sex.Med.Today 1985;9:8-12. (6) Porpora MG,.Gomel V. The role of laparoscopy in the management of pelvic pain in wom- en of reproductive age. Fertil.Steril. 1997;68:765-79. (7) Campbell RM. Anatomy and physiology of sacrouterine ligaments. Am J Obstet Gynecol 1950;59:1. (8) Davis A. Intrinsic dysmenorrhoea. Proc R Soc Med 1936;29:931. (9) Frankenhauser G. Die Bewegungenerven der Gebarmutter. Z Med.Nat Wiss 1864;1:35. (10) Latarjet A,.Roget P . Le plexus hypogastrique chez la femme. Gynecologie et Obstetrique 1922;6:225. (11) Proctor ML, Latthe PM, Farquhar CM, Khan KS, Johnson NP . Surgical interruption of pel- vic nerve pathways for primary and secondary dysmenorrhoea. The Cochrane Database of Systematic Reviews 2005, 4. (12) Clarke MJ,.Stewart LA. Meta-analyses using individual patient data. J Eval.Clin Pract. 1997;3:207-12. (13) Stewart LA,.Parmar MK. Meta-analysis of the literature or of individual patient data: is there a difference? Lancet. 1993;341:418-22. (14) Stewart LA,.Clarke MJ. Practical methodology of meta-analyses (overviews) using up- dated individual patient data. Cochrane Working Group. Stat Med. 1995;14:2057-79. (15) Chen FP , Chang SD, Chu KK, Soong YK. Comparison of laparoscopic presacral neurec- tomy and laparoscopic uterine nerve ablation for primary dysmenorrhea. J Reprod Med 1996;41:463-6. (16) Johnson NP , Farquhar CM, Crossley S, Yu Y, van Peperstraten AM, Sprecher M et al. A double-blind randomised controlled trial of laparoscopic uterine nerve ablation (LUNA) for women with chronic pelvic pain. BJOG 2004;111:950-9. (17) Lichten EM,.Bombard J. Surgical treatment of primary dysmenorrhea with laparoscopic uterine nerve ablation. J Reprod.Med. 1987;32:37-41. (18) Sutton C, Pooley AS, Jones KD, Dover RW, Haines P . A prospective, randomized, dou- ble-blind controlled trial of laparoscopic uterine nerve ablation in the treatment of pelvic pain associated with endometriosis. Gynaecol Endosc 2001;10:217-22. LUNA IPD Meta-analysis protocol 84 (19) The LUNA Trial Collaboration. A randomised controlled trial to assess the efficacy of Lap- aroscopic Uterosacral Nerve Ablation (LUNA) in the treatment of chronic pelvic pain: The trial protocol [ISRCTN41196151]. BMC.Womens Health 2003;3:6. (20) Vercellini P , Aimi G, Busacca M, Apolone G, Uglietti A, Crosignani PG. Laparoscopic uterosacral ligament resection for dysmenorrhea associated with endometriosis: results of a randomized, controlled trial. Fertil.Steril. 2003;80:310-9. (21) Yen YK, Liu WM, Yuan CC, Ng HT. Addition of laparoscopic uterine nerve ablation to laparoscopic bipolar coagulation of uterine vessels for women with uterine myomas and dysmenorrhea. J Am Assoc.Gynecol Laparosc. 2001;8:573-8. Chapter 6 85 LUNA IPD Meta-analysis protocol 86 87 Chapter 7 Individual patient data meta-analysis of randomised evidence to assess the effectiveness of laparoscopic uterosacral nerve ablation in chronic pelvic pain 88 Chapter 7

Background: There have been conflicting results in randomised trials of the effects of laparo- scopic uterosacral nerve ablation (LUNA) in chronic pelvic pain. Our objective was to perform a meta-analysis using individual patient data (IPD) to provide the most comprehensive and reliable assessment of the effectiveness of LUNA.

Electronic searches were conducted in the Medline, Embase, PsycInfo and Cochrane Library databases from database inception to August 2009. The reference lists of known relevant papers were searched for any further articles. Randomised trials comparing LUNA with no ad- ditional intervention were selected and authors contacted for IPD. Raw data were available from 862 women randomised into five trials. Pain scores were calibrated to a 10 point scale and were analysed using a multilevel model allowing for repeated measures.

There was no significant difference between LUNA and No LUNA for the worst pain recorded over a 12 month time period (mean difference 0.25 points in favour of No LUNA on a 0-10 point scale, 95% CI -0.08 to 0.58; p=0.1).

LUNA does not result in improved chronic pelvic pain.

Chronic pelvic pain, defined as lower abdominal pain or pelvic pain of longer than 6 months’ duration, is a common condition. 1 It has multiple causes, 2 and prevalence varies widely glob- ally.3 It remains one of the most challenging of women’s health problems with a major impact on health-related quality of life, productivity,4 and health care utilisation, costing an estimated £250 million (at 2005/06 prices) on its management in the UK.5 Only 20-25% patients respond to initial conservative management.6 When such treatment fails, a diagnostic laparoscopy is frequently performed.7 The cause of the pain is not always obvious as no pathology is seen in 35% (range 3-92%) of the cases.8,9 In the absence of pathology there is no established gynaecological treat- ment. Interruption of the Lee-Frankenhauser sensory nerve plexuses by laparoscopic uterosacral nerve ablation (LUNA) may alleviate pain. 10,11 LUNA can be carried out quickly and simply alongside diagnostic laparoscopy using lasers or electro-diathermy and has become widely practised, 12,13 Chapter 7 89 although clinicians’ beliefs about its effectiveness vary widely. 14 The effects of this intervention have been assessed in randomised controlled trials 15-19 and summarised in published data sys- tematic reviews.20-22 In a Cochrane review of surgical interruption for primary and secondary dysmenorrhoea,21 there was some evidence of the effectiveness of LUNA when compared to a control or no treatment in the absence of endometriosis (odds ratio 6.1, 95% confidence interval 1.8 to 21.0), but not for secondary dysmenorrhoea (0.8, 95% CI -0.4 to 1.4). These reviews concluded that there is insufficient evidence to recommend the use of nerve interruption in the management of dysmenorrhoea, regardless of cause, which was reiterated by the UK National Institute of Health and Clinical Excellence.23 Meta-analysis using individual patient data (IPD) from primary studies has the potential to pro- duce a more reliable estimate of treatment effect than from meta-analysis of aggregate data and also to allow exploration of sub-groups. 24,25 The LUNA IPD Meta-analysis Collaborative Group, a consortium of authors of all primary studies involving LUNA, was established to use these ad- vanced analytic techniques to evaluate the effectiveness of LUNA in reducing chronic pelvic pain.

We undertook an IPD meta-analysis to examine the effectiveness of LUNA in reducing chronic pelvic pain according to a pre-specified protocol,26 developed using recommended methods.27 Search Strategy The search methods previously described 21 were updated in August 2009 (from 2003 to current) to identify any trials published since the last search and to identify ongoing trials to seek unpub- lished data. A comprehensive database was constructed using Reference Manager 12.0 to store all identified references. No language restrictions were applied. Study inclusion and data collection Studies were considered for inclusion if LUNA, as an intervention for women of reproductive age with CPP , primary or secondary dysmenorrhoea, was compared against diagnostic laparoscopy in a randomised controlled trial. Trials with concomitant ablation of endometrial lesions were in- cluded provided ablation was an option in both study groups. Two reviewers (JPD, RC) indepen- dently assessed trials for inclusion and quality, with queries resolved by a third reviewer (KSK). Criteria for quality assessment were based initially on the reported characteristics and included adequacy of sequence generation and allocation concealment; blinding of participants, and as- sessors where used, to treatment allocation; intention to treat analysis performed and potential impact of losses of follow-up data. LUNA IPD Meta-analysis 90 Primary authors of included randomised trials were invited to join the collaborative group and to provide anonymised raw data on visual analogue score (VAS) pain ratings, the presence or absence of visual pathology, age at randomisation and parity. Further assessment of data quality on receipt of the dataset included the ability to reproduce the published results and discrepant patterns of data. Where discrepancies existed authors were contacted for clarification. Statistical Analysis The primary outcome was a derived measure of worst pain level experienced if data was re- ceived on different pain symptoms (e.g. dysmenorrhoea, non-cyclical pain and dyspareunia). Pain scores using a visual analogue scale (VAS) were rescaled where necessary, to anchor the scale between zero (no pain) and ten (worst pain imaginable). Rather than dichotomising the data at an arbitrary threshold, as was the case in two of the included studies, 16,17 scores were evalu- ated as a continuous measurement, thus improving the precision of the analysis. 28 A clinically significant difference in pain has been defined as 2 points on a 10-point VAS for chronic pelvic pain 29 and elsewhere, moderately important difference equates to at least a 30% reduction of the 10-point VAS for pain.30 Where study information was available on allocated and received treatments, the intention to treat principle was used to analyse the data. Comparisons between allocation groups, using data up to and including 12 months, were performed using multilevel modelling techniques in SAS PROC MIXED, using all available data to estimate treatment effects over time. 31 The pri- mary analysis model included covariate parameters for trial (to take account of differing sized trials), allocation group, baseline score and time, the latter nested within patient and trial. 32,33 Heterogeneity of treatment effects across trials was investigated by including a trial by treatment interaction term in the model. 34 Where this test was statistically significant (a value of p<0.05 used here), sensitivity analysis were undertaken to investigate any existing inconsistency in the data. Secondary analyses incorporating the allocation group as a random effect were also undertaken for the primary analysis. Restricted maximum likelihood estimates of the overall treatment effect were calculated along with 95% confidence intervals. Subgroup analysis, including any differential treatment effect over time, was explored in a similar fashion by adding the relevant parameter by treatment interaction term to the basic model. Pre- defined subgroup analyses were the presence or absence of visual pathology (endometriosis, adhesions, pelvic inflammatory disease) and site of pain (central versus peripheral), as some tri- als reported differential effects. 17,35 Additional subgroups that could feasibly impact on treatment effects and for which data were available were age group (<30 years, ≥30 years at randomisa- tion) and parity (nulliparous, parous). Treatment effect estimates within subgroups were further investigated, alone, and where necessary in combination, if the relevant interaction terms were statistically important at p<0.05. Chapter 7 91

Trials and patients A total of 56 citations were identified by electronic searches (Figure 1). After detailed evaluation of the papers and removal of four duplicates, five primary articles met the selection criteria and were included.15-19 Trials were excluded due to a lack of an adequate method for generating allocation sequence for randomisation,(36) if they used an intervention not within the scope of this meta-analysis,35,37,38 did not have a non-interventional control, 39-42 or could not assess the individual contribution of LUNA.43 Figure 1: Study selection process for the individual patient data meta-analysis to assess the effectiveness of laparoscopic uterosacral nerve ablation (LUNA) in chronic pelvic pain. The characteristics of all included studies in the analysis are summarized in the Table 1. The interventions in experimental and control arms were comparable across all trials. Trial popula- tions comprised women with CPP with or without visible pathology, apart from one,19 which only assessed LUNA for primary dysmenorrhea. IPD was received for all five (100%) of the included trials, which involved 862 randomised women. 1 FIGURES Figure 1: Study selection process for the individual patient data meta-analysis to assess the effectiveness of laparoscopic uterosacral nerve ablation (LUNA) in chronic pelvic pain Articles excluded n = 13 - Duplicates n = 4 - Comparison not of interest n = 7 - Unable to distinguish effect of LUNA n = 1 - Not randomised n = 1 Citations excluded after screening titles/ abstracts n = 38 Articles included in systematic review n = 5 (862 women randomised) Total citations identified from electronic searches n = 45 Articles retrieved for evaluation n = 7 Articles identified through the Cochrane Library n = 11 Total articles retrieved for detailed evaluation n = 18 LUNA IPD Meta-analysis Table 1 Table of characteristics of included studies in the individual patient data meta-analysis to assess the effectiveness of laparoscopic uterosacral nerve ablation in chronic pelvic pain. Studies Lichten 1987 Sutton 2001 Vercellini 2003 Johnson 2004 Daniels 2009

Allocation concealment Inadequate. Adequate, sealed envelopes Adequate, sealed envelopes Adequate, sealed envelopes Adequate, third party randomisation Randomisation Randomised by last digit of medical case number on day of surgery. Computer- generated randomisation sequence Computer- generated randomisation sequence Computer-generated randomisation sequence Computer- generated randomisation sequences using minimisation Blinding Double blinding: participant and clinical psychologist. Double blinding; participant and research nurse. Open Double blinding; participant and investigator. Single blinding; only patient blinded, no evaluator in this trial Follow-up 3 and 12 months 6 and 12 months 24 hours, 3 and 12 months 3,6 and 12 months and 2, 5 and 10 yrs Number of women randomised 21 51 180 123 (56 with no endometriosis) 487 (266 with no pathology) Number of women in primary analysis 21 at 12 months 46 at 6 months 116 at 12 months 106 at 12 months 378 at 12 months Drop-outs/ withdrawals None. 5 (1 became pregnant and 4 were lost to follow up). However data points for to 14 women were missing for some analyses. 29 pregnant, 14 used oral contraception, 15 lost to follow-up, 6 miscellaneous reasons. 14 were excluded based on laparoscopic findings. Loss to follow up: 24 hours: 1 3 months: 3 (2 LUNA and 0 no LUNA in the population with no endometriosis; 0 LUNA and 1 no LUNA in the endometriosis population). 12 months: 17 (4 LUNA and 2 no LUNA in the population with no endometriosis; 6 LUNA and 5 no LUNA in the endometriosis population). Withdrawals: 6 (3 LUNA 3 No LUNA) before 12 months Lost to follow-up: 18 (11 LUNA 8 no LUNA) provided no data up and including 12 months. Quality Compliance with quality criteria (out of 5) 2 4 3 4 4 Inclusion Criteria Women with severe dysmenorrhoea. No improvement during run- in phase on medication or oral contraceptive. Women with history and physical or laparoscopic examination suggestive of endometriosis who had not received medical treatment for endometriosis within the last 6 months, and had not previously undergone surgical treatment of their disease Women aged 18 to 40, who reported pelvic pain of more than 6 months duration; undergoing operative laparoscopy for symptomatic minimal to severe endometriosis Women aged 18 to 45 years, who reported pelvic pain of more than 6 months duration; no change in medication in previous 3 months. Women who reported pelvic pain of 6 months or longer in duration, located within the true pelvis or between and below the anterior iliac crests; associated functional disability; lack of response to medical treatment; undergoing diagnostic laparoscopy. Chapter 7 93 Studies Lichten 1987 Sutton 2001 Vercellini 2003 Johnson 2004 Daniels 2009 Exclusion Criteria History of psychotherapy, major abdominal procedures, drug abuse; demonstrable pelvic pathology at diagnostic laparoscopy. Severe endometriosis, any other pathology that may have been responsible for their pain symptoms; currently pregnant or intending to get pregnant; medical treatment for endometriosis within last 6 months; previous surgery for endometriosis. Previous diagnosis of endometriosis; any other pathology that may have been responsible for their pain symptoms, presence of vaginal endometriosis; treatment for endometriosis other than nonsteroid anti- inflammatory drugs up to 6 months before entry in the study; previous diagnosis of gastrointestinal, urologic and orthopedic diseases in which pain may radiate to the pelvic area; known psychiatric disturbances. Previous hysterectomy or pelvic malignancy; previous LUNA; known ovarian cysts; pelvic adhesions which did not appear to be due to endometriosis; plan for a pregnancy within 12 months; intention to change other medical treatment which could influence pelvic pain scores within 12 months; LUNA technically not possible. Previous hysterectomy; previous LUNA; moderate and severe endometriosis; previous surgery for endometriosis or pelvic inflammatory disease; adnexal pathology; LUNA technically not possible. Primary dysmenorrhoea CPP with minimal to moderate pelvic endometriosis Secondary dysmenorrhoea (minimal to severe endometriosis) CPP with no visible pathology or with minimal to severe endometriosis CPP with no visible pathology or minimal to mild endometriosis, mild pelvic inflammatory disease, minimal adhesions Age Range 18-34. Mean for each group not given. Mean 28 (range 20 to 41). Mean for each group not given, but stated no difference. Range 18-40. Mean for each group not given. Mean (SD) No endometriosis group LUNA 29 (5.83) No LUNA 29 (6.49) With endometriosis group LUNA 30 (6.71) No LUNA 29 (5.31) Mean (SD) LUNA 30·6 (7·53) No LUNA 30·5 (7·48) Location Detroit, USA Surrey, UK Milan, Italy Auckland, New Zealand Multicentre, UK Treatment LUNA LUNA with laparoscopic excision or ablation of all visible endometriosis. LUNA with laparoscopic excision or ablation of all visible endometriosis Group with endometriosis: LUNA with laparoscopic excision or ablation of all visible endometriosis Group without endometriosis: LUNA Group with pathology: LUNA with laparoscopic excision or ablation of all visible endometriosis and/ or adhesionolysis. Group without pathology: LUNA Control Diagnostic laparoscopic surgery only. Laparoscopic excision or ablation of visible endometriosis. Laparoscopic excision or ablation of visible endometriosis. Group with endometriosis: laparoscopic excision or ablation of visible endometriosis Group without endometriosis: diagnostic laparoscopic surgery only. Group with pathology: laparoscopic excision or ablation of visible endometriosis and/ or adhesionolysis. Group without pathology: diagnostic laparoscopic surgery only. LUNA IPD Meta-analysis 94 The methodological quality of the included studies was generally good, with adequate randomi- sation and blinding of the participants and assessors, where employed (Figure 2). In one trial, 19 randomisation was inadequately concealed so was excluded from the primary analysis, although a sensitivity analysis including these data was conducted. On receipt of raw data, it was not possible to guarantee an intention-to-treat analysis for two studies,16,18 as provided data did not give details on allocated and received procedures. In one of these studies, a problem with the database precluded use of all but the baseline and three months data. Figure 2 Mean pain scores over time for trials included in the analysis. Lower score indicates less pain. Effectiveness of LUNA on relieving pain In all trials, a marked improved in pain scores was seen in both LUNA and No LUNA groups following laparoscopy. Dysmenorrhoea was invariably the worst pain reported. In the primary analysis, the No LUNA group demonstrated a non-significant greater improvement in their worst pain score than the LUNA group when a constant treatment effect over time was assumed (0.25 points on a 10-point scale, 95%CI -0.08 to 0.58; p=0.1). This result was consistent over the four 2 Figure 2: Mean pain scores over time for trials included in the analysis. Lower score indicates less pain. Chapter 7 95 high quality trials (test for trial by treatment interaction: p=0.2) (Figure 3). A similar difference was seen when the treatment effect was allowed to vary randomly over the trials (0.32 points, 95%CI -0.40 to 1.05; p=0.3). Likewise, including the inadequately concealed trial as a sensitivity analysis did not change the overall result (0.1 points, 95%CI -0.23 to 0.44; p=0.5), but significant het- erogeneity between trials was introduced (p<0.0001) and so no further examination of the data including this trial was undertaken. The observed treatment effect was demonstrated to change over time (test for time by treatment interaction p=0.004); a difference in pain improvement in favour of No LUNA was seen at 3 months (0.49 points, 95%CI 0.12 to 0.86; p=0.009), but not at 6 months (0.25 points, 95%CI -0.09 to 0.58; p=0.1) or 1 year (-0.25 points, 95%CI -0.72 to 0.23; p=0.3) (Figure 3). Figure 3 The bottom graph shows the maximum likelihood estimates of visual analogue pain scores from a multilevel model with timepoint nested within patient, within trial and with baseline score as a covariate and treatment effect allowed to vary over time. Mean pain score are meas- ured on a visual analogue scale of 0 (no pain) to 10 (worst imaginable pain).The top graph shows the difference in mean visual analogue scale (VAS) pain scores, with error bars indicating 95% confidence intervals. There was some evidence that presence of visible pathology altered the effectiveness of LUNA (p=0.01) (Table 2).Where pathology was present, the No LUNA group had greater improvement in pain at 3 months (0.81 points, 95%CI 0.36 to 1.26; p=0.0004) and 6 months (0.61 points, 95%CI 0.19 to 1.04; p=0.005), whereas those without visible pathology benefited more from 3 Figure 3: The bottom graph shows the maximum likelihood estimates of visual analogue pain scores from a multilevel model with timepoint nested within patient, within trial and with baseline score as a covariate and treatment effect allowed to vary over time. Mean pain score are measured on a visual analogue scale of 0 (no pain) to 10 (worst imaginable pain).The top graph shows the difference in mean visual analogue scale (VAS) pain scores, with error bars indicating 95% confidence intervals. No LUNA superior LUNA IPD Meta-analysis 96 LUNA at 1 year (-0.68 points, 95%CI -1.29 to 0.07; p=0.03), but not at 3 or 6 months. There was no evidence that age (p=0.1) or parity (p=0.7) had any differential effect on the treatment effect when these parameters were assessed in the model, so combinations of subgroups were not investigated further. Only one trial provided data on site of pain, so this subgroup analysis was not attempted. There were no reports of serious peri-operative or subsequent adverse events. Table 2 Subgroup analysis of presence or absence of pathology on the effect of LUNA in al leviating pain

Main findings Our review provides the most comprehensive and reliable means of assessing the effectiveness of LUNA in women with CPP in whom diagnostic laparoscopy reveals either no or minimal pa- thology. LUNA did not alleviate pain compared to the No LUNA group, indeed there was some evidence that women who have the LUNA procedure may suffer from more pain in the short term than those who do not. Contradictory treatment effects were seen in the presence and absence of pathology, but were not consistent at every timepoint, whereas age and parity did not influence the treatment effect. Strengths and limitations of the review The availability of individual patient data from all included studies enabled a more thorough inves- tigation of overall and subgroup treatment effects than previous meta-analyses have achieved. Problems with database relational integrity prompted us to exclude some data from the meta- analysis. One lower quality study, which was clinically and statistically heterogeneous to the other studies was excluded from the primary analyses, although sensitivity analysis indicated this had no effect on the overall treatment effect. The multilevel model accounting for repeated measures increased the accuracy of estimates by using continuous pain scores, rather than dichotomised Timepoint Pathology present Mean VAS difference (95% confidence interval), p-value for difference Pathology absent Mean VAS difference (95% confidence interval), p-value for difference 3 months 0.81 (0.36,1.26) p=0.0004 -0.08 (-0.66,0.50) p=0.8 6 months 0.61 (0.19,1.04) p=0.005 -0.28 (-0.82,0.26) p=0.3 12 months 0.21 (-0.35,0.78) p=0.5 -0.68 (-1.29,-0.07) p=0.03 Test for heterogenetity between subgroups p=0.01 Mean VAS difference of worst pain score between LUNA and No LUNA groups. Positive number indicates greater improvement in No LUNA group Chapter 7 97 measures of success used in some trials. 16,17 With IPD, we were able to explore the variation between subgroups and treatment effects within subgroups, using similar statistical models. Un- like previous meta-analyses,21 we chose to exclude trials with interventional controls in order to assess LUNA’s efficacy in pain relief, therefore cannot comment on its effectiveness compared to presacral neurectomy. There were no other outcome measures common to included studies, so analyses were restricted to pain reduction. Interpretation This IPD meta-analysis reinforces the conclusions drawn from the largest trial of LUNA 15 that the procedure is not effective in alleviating pain within one year of treatment. Although a long term assessment of LUNA was not possible here due to lack of data beyond 12 months from most primary studies, the UK LUNA trial does not suggest any delayed effect of LUNA. Subgroup analysis did suggest a benefit of LUNA in those without visible pathology, consistent with the Cochrane review, although this effect was only seen at 12 months and was of borderline sta- tistical significance. 21 Conversely, the IPD meta-analysis of those with visible pathology showed greater decrease in pain in the No LUNA group, contradicting the Cochrane review. These sub- group effects lack biological plausibility and are likely to have arisen by chance. Moreover, given that a clinically significant difference in pain has been defined as 2 points on a 10-point visual analogue scale for chronic pelvic pain, 29,30 and also for other types of pain,44 it seems implausible that LUNA could produce a clinically relevant effect in women with minimal gynaecological pa- thology. In every comparison, the confidence intervals around the mean difference in pain scores between the groups were less than ±0.7 points: in our statistically significant subgroup analysis, at 12 months in the absence of pathology, the pain score was 0.68 points lower with LUNA and the upper 95% confidence interval was 1.29 points lower, well below a clinically significant improvement. The meta-analysis conclusively dismisses the use of LUNA for all women with pelvic pain in the presence of visible pathology,, and strongly suggests that LUNA does not provide any benefit of clinical importance for women without recognisable pathology, due to lack of efficacy. National guidelines should be updated and brought in line with that of the UK. 23 There is no need for any further randomized controlled trials of LUNA and future research should focus on further investi- gation of the causes of chronic pelvic with a view to identifying novel treatments or refining exist- ing therapies and assessing their effectiveness in large, well designed randomized trials. Lack of efficacy in this study, and others (Personal communication E Lichten), provide strong evi- dence that the pathophysiology of chronic pelvic pain is complicated and a greater understand- ing of the interaction of neural pathways and uterine physiology is needed to direct research of further interventions. LUNA IPD Meta-analysis 98 An additional aim was to motivate the collaborating primary investigators to undertake new, mutually planned, primary studies in this field. Few IPD meta-analysis have been published in gynaecological research to date and it is hoped this paper, alongside other international initia- tives (www.ipd-meta-analysis.com) will motivate others to adopt this technique when uncertainty remains despite published data meta-analysis.

We naturally want to thank the International LUNA IPD Meta-analysis Collaborative Group for kindly providing the data, responding to the various queries raised and providing valuable feed- back on the draft paper. The authors would like to thank the Wellbeing of Women, a registered UK charity, for providing the financial support for the original UK LUNA clinical trial and continued support to produce this IPD meta-analysis. They would also like to thank Tai-In Um for translation of the paper by Moon et al from Korean. Chapter 7 99

1 Zondervan KT, Yudkin PL, Vessey MP , Dawes MG, Barlow DH, Kennedy SH Prevalence and incidence of chronic pelvic pain in primary care: evidence from a national general practice database. BJOG 1999;106(11):1149-55. 2 Latthe P , Mignini L, Gray R, Hills R, Khan K. Factors predisposing women to chronic pel- vic pain: systematic review. BMJ 2006;332(7544):749-51. 3 Latthe P , Latthe M, Say L, Gulmezoglu M, Khan KS. WHO systematic review of prev- alence of chronic pelvic pain: a neglected reproductive health morbidity. BMC Public Health 2006;6(1):177. 4 Sundell G, Milsom I, Andersch B. Factors influencing the prevalence and severity of dys- menorrhoea in young women. BJOG 1990;97(7):588-94. 5 Davies L, Ganger K, Drummond M, Saunders D, Beard R. The economic burden of in- tractable gynaecological pain. J Obstet Gynaecol 1992;12(S2):54-6. 6 Henzl M.R. Dysmenorrhoea; achievements and challenge. Sex Med Today 1985;9:8-12. 7 Royal College of Obstetricians and Gynaecologists: Guidelines and Audit Committee. The initial management of chronic pelvic pain. 2005. Guideline 41. 8 Porpora M, Gomel V. The role of laparoscopy in the management of pelvic pain in women of reproductive age. Fertil Steril 1997;68(5):765-79. 9 Howard FM. The role of laparoscopy as a diagnostic tool in chronic pelvic pain. Best Pract Res Clin Obstet Gynaecol 2000;14(3):467-94. 10 Doyle JB. Paracervical uterine denervation by transection of the cervical plexus for the relief of dysmenorrhoea. Am J Obstet Gynecol 1955;70:1. 11 Doyle JB, Des Rosiers JJ Paracervical uterine denervation for the relief of pelvic pain. Clinical Obstet Gynecol 1963;6:742-53. 12 Daniels J, Gray R, Khan K, Gupta J. Laparoscopic uterine nerve ablation: A survey of gynaecological practice in the UK. Gynaecol Endosc 2000;9(3):157-9. 13 Latthe P , Powell R, Daniels J, Hills RK, Gray R, Gupta JK, et al. Variation in practice of Laparoscopic uterosacral nerve ablation: A European survey. J Obstet Gynaecol 2004;24(5):547-51. 14 Latthe PM, Braunholtz DA, Hills RK, Khan KS, Lilford R. Measurement of beliefs about ef- fectiveness of laparoscopic uterosacral nerve ablation. BJOG 2005;112(2):243-6. 15 Daniels J, Gray R, Hills RK, Buckley L, Gupta J, Latthe P , et al. Laparoscopic uterosa- cral nerve ablation for alleviating chronic pelvic pain: a randomized controlled trial. JAMA 2009;302(9):955-61. 16 Vercellini P , Aimi G, Busacca M, Apolone G, Uglietti A, Crosignani PG. Laparoscopic uterosacral ligament resection for dysmenorrhea associated with endometriosis: results of a randomized, controlled trial. Fertil Steril 2003 Sep;80(2):310-9. LUNA IPD Meta-analysis 100 17 Johnson NP , Farquhar CM, Crossley S, Yu Y, van Peperstraten AM, Sprecher M, et al. A double-blind randomised controlled trial of laparoscopic uterine nerve ablation (LUNA) for women with chronic pelvic pain. BJOG 2004;111(9):950-9. 18 Sutton C, Pooley AS, Jones KD, Dover RW, Haines P . A prospective, randomized, dou- ble-blind controlled trial of laparoscopic uterine nerve ablation in the treatment of pelvic pain associated with endometriosis. Gynaecol Endosc 2001;10(4):217-22. 19 Lichten EM, Bombard J. Surgical treatment of primary dysmenorrhea with laparoscopic uterine nerve ablation. J Reprod Med 1987;32(1):37-41. 20 Khan KS, Khan SF, Nwosu CR, Dwarakanath LS, Chien PFW. Laparoscopic uterosacral nerve ablation in chronic pelvic pain: An overview. Gynaecol Endosc 1999;8(5):257-65. 21 Proctor ML, Latthe PM, Farquhar CM, Khan KS, Johnson NP . Surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2005;4. 22 Stones RW, Mountfield J. Interventions for treating chronic pelvic pain in women. Cochrane Database Syst Rev 2000;4. 23 National Institute for Health and Clinical Excellence. Laparoscopic uterine nerve ablation (LUNA) for chronic pelvic pain. London; 2007. Report No. IPG234. 24 Stewart LA, Clarke MJ. Practical methodology of meta-analyses (overviews) using indi- vidual patient data. Cochrane Working Group. Stat Med 1995;14(19):2057-79. 25 Stewart LA, Tierney JF. To IPD or not to IPD? Advantages and disadvantages of system- atic reviews using individual patient data. Eval Health Prof 2002;25(1):76-97. 26 Xiong T, Daniels J, Middleton L, Champaneria R, Khan KS, Gray R, et al. Meta-analysis using individual patient data from randomised trials to assess the effectiveness of lapa- roscopic uterosacral nerve ablation in the treatment of chronic pelvic pain: a proposed protocol. BJOG 2007;114(12):1580, e1- e7. 27 Stewart LA, Tierney JF, larke M. Reviews of individual patient data. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions. 5.01 ed. The Cochrane Collaboration; 2008. 28 Altman DG, Royston P . The cost of dichotomising continuous variables. BMJ 2006;332(7549):1080. 29 Baker PN, Symonds EM. The resolution of chronic pelvic pain after normal laparoscopy findings. Am J Obstet Gynecol 1992;166(3):835-6. 30 Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain 2008;9(2):105-21. 31 Higgins JP , Whitehead A, Turner RM, Omar RZ, Thompson SG. Meta-analysis of continu- ous outcome data from individual patients. Stat Med 2001;20(15):2219-41. 32 Jones AP , Riley RD, Williamson PR, Whitehead A. Meta-analysis of individual patient data versus aggregate data from longitudinal clinical trials. Clin Trials 2009;6(1):16-27. Chapter 7 101 33 Brown H, Prescott R. Applied Mixed Models in Medicine. Wiley, Chichester; 2006. 34 Whitehead A. Meta-Analysis of Controlled Clinical Trials. Wiley, Chichester; 2002. 35 Tjaden B, Schlaff WD, Kimball A, Rock JA. The efficacy of presacral neurectomy for the relief of midline dysmenorrhoea. Obstet Gynecol 1990;76:89-91. 36 Moon M.J. The clinical significance of laparoscopic uterosacral nerve ablation (LUNA). Korean J Obstet Gynecol 2001;44(12):2224-8. 37 Candiani GB, Fedele L, Vercellini P , Bianchi S, Di Nola G. Presacral neurectomy for the treatment of pelvic pain associated with endometriosis: a controlled study. Am J Obstet Gynecol 1992;167(1):100-3. 38 Zullo F, Pellicano M, DeStefano R. Efficacy of Laparoscopic Pelvic Denervation in Central- type Chronic Pelvic Pain: A multicentre study. J Gynecol Surg 1996;12:35-40. 39 Chen FP , Chang SD, Chu KK, Soong YK. Comparison of laparoscopic presacral neurec- tomy and laparoscopic uterine nerve ablation for primary dysmenorrhea. J Reprod Med 1996;41(7):463-6. 40 Garcia LF, Oviedo OG, Reyes CH, Ibarrola BE, Von der MW. Presacral neurectomy and uterine nerve ablation in chronic pelvic pain. Laparoscopic management. A comparative study. Ginecol Obstet Mex 2003;71:137-42. 41 Juang CM, Chou P , Yen MS, Horng HC, Twu NF, Chen CY. Laparoscopic uterosacral nerve ablation with and without presacral neurectomy in the treatment of primary dys- menorrhea: a prospective efficacy analysis. J Repro Med 2007;52(7):591-6. 42 Yen YK, Liu WM, Yuan CC, Ng HT. Addition of laparoscopic uterine nerve ablation to laparoscopic bipolar coagulation of uterine vessels for women with uterine myomas and dysmenorrhea. J Am Assoc Gynecol Laparosc 2001;8(4):573-8. 43 Sutton CJ, Ewen SP , Whitelaw N, Haines P . Prospective, randomized, double-blind, con- trolled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertil Steril 1994;62(4):696-700. 44 Biljsma JW. Patient centred outcomes in arthritis. Ann Rheum Dis 2007;64:1-2. LUNA IPD Meta-analysis 102 103 Chapter 8 Psychological Therapies for Chronic Pelvic Pain: Systematic review of Randomized Controlled Trials 104 Chapter 8

Chronic Pelvic Pain (CPP), a common cause of disability in women, is a condition best viewed in the biopsychosocial framework. Psychological interventions are frequently considered alongside medical and surgical treatments. Our objective was to evaluate the effectiveness of psychological therapies for the treatment of CPP . Electronic literature searches were conducted in Medline, Embase, PsycInfo and DARE data- bases from database inception to April 2010. Reference lists of selected articles were searched for further articles. The studies selected were randomized controlled trials of psychological therapies in patients with CPP compared to no treatment, standard gynecological treatment or another form of psy- chological therapy. Two reviewers independently selected articles without language restrictions, and extracted data covering study characteristics, study quality and results. Reduction in pain, measured using visual analog scales or other measurements, was the main outcome measure. Of the 107 citations identified, four studies satisfied the inclusion criteria. Compared to no psy- chological intervention, therapy produced a standardized mean pain score of -3.27 (95% CI -4.52 to -2.02) and 1.11 (95% CI -0.05 to 2.27) at 3 months and -3.95 (95% CI -5.35 to -2.55) and 0.54 (95% CI -0.78 to 1.86) at 6 months and greater, based on a visual analog scale score of 0-10. The current evidence does not allow us to conclude whether psychological interventions have an effect on self reported pain scores in women with CPP .

Chronic Pelvic Pain (CPP), defined as constant or intermittent, cyclic or acyclic pain lasting 6 months or more, is a common condition. 1 Symptoms include dysmenorrhea, deep dyspareunia and intermenstrual pain2. Up to 15% of women consulting primary care physicians and 40% of women consulting gynecologists in secondary care complain of CPP . 3-6 A definite diagnosis and effective treatment of CPP is not straightforward, as it can be a symptom of another condition such as endometriosis, or a syndrome in its own right, without an identifiable cause. 7,8 Chapter 8 105 Chronic Pelvic Pain is perhaps best seen from a biopsychosocial perspective whereby patho- physiology, health beliefs, psychological well-being and social situations all contribute to the women’s experience of pain and lead to the adoption of coping strategies which may have an impact on the women’s wellbeing.8 Women with CPP are more likely to have experienced abuse, either physical or psychological, miscarriage, Cesarean section or drug or alcohol dependency than controls without pain. 9 Psychological interventions are frequently considered alongside medical and surgical treatments. Although psychological therapies are widely used to treat other forms of pain, and there is good evidence to support this practice, there is a surprising lack of evidence for its use to treat CPP . A Cochrane review, 10 looked at randomized controlled trials (RCTs) of behavioral interventions for primary and secondary dysmenorrhea but not CPP . In this review, we examine whether psychological interventions are effective in treating idiopathic CPP , by looking at all relevant published RCTs.

The systematic review was conducted based on a prospective protocol designed using widely recommended methods. 11,12,13 No ethical approval was needed for this review. Identification of studies A sensitive search strategy was developed. The following databases were searched: Embase, Medline, PsycInfo, DARE and the Cochrane Library from database inception to April 2010. Our search term combinations consisted of MeSH subheading, text words, and word variations for the concepts ‘Psychological Therapy’ and ‘chronic pelvic pain’. These were combined with filters for studies of effectiveness. For the purposes of this review, the term ‘psychological therapy’ was used to encompass all therapies which address mental health problems or psychological issues associated with CPP through structured therapeutic conversations with trained thera- pists, with an emphasis on a reflective, experiential process. Such therapies aim to help patients change behavior, cognitions or mood which exacerbates or maintains problems. 14 The umbrella term ‘Psychological Therapy’, encompassed therapies including Cognitive Behavior Therapy, counseling, art ,music and writing therapies, psychoanalysis, psychotherapy, psychiatry, Gestalt therapy, group therapy, integrative psychotherapy, psychoanalytic therapy, interpersonal therapy, psychodynamic therapy, person/ client centered therapy, systemic therapy, nondirective therapy and Neurolinguistic Programming. These terms characterizing the different forms of psychologi- cal therapy were found by conducting a scoping search looking at dictionaries and textbooks for definitions of ‘Psychological therapies’. Results from this were then used to perform a simple literature search in a handful of bibliographic databases to establish what phrases/ keywords were being yielded when a broad term such as ‘psychological therapies’ was searched for. Systematic Review of Psychological Therapies for CPP 106 All identified search terms then went on to form the final search strategy. This search strategy was adapted to suit each database and was restricted to humans and females. We also hand searched the bibliographies of all relevant primary articles and reviews to identify articles missed by the electronic searches. A comprehensive database was constructed using Reference Man- ager 12.0 (Thomson Reuters) to store all identified references. No language restrictions were applied. Study selection and data extraction procedures Studies were selected in two steps. First we scrutinized the citations identified by the electronic searches and obtained full manuscripts of all the citations that met or were thought to have met the predetermined inclusion criteria. Two reviewers (AR, RC), then independently inspected all of the manuscripts to determine if they met the following criteria: 1. Population: Women with CPP (of unknown etiology) 2. Interventions: Psychological or behavioral therapies 3. Comparator: No treatment, standard gynecological treatment or another form of psycho- logical therapy. 4. Outcomes: Pain relief or symptom improvement 5. Study design: Randomized controlled trial (RCT) In case of duplicate publications the most recent and complete versions were used. We extract- ed data on study characteristics and methods onto a pre-designed pro-forma. Any disagree- ments surrounding the selection of a manuscript or data extraction were resolved by consensus or arbitration by a third reviewer (JD, KSK or HMP). Methodological quality assessment All manuscripts meeting the selection criteria were assessed for their methodological quality, defined as the confidence that the study design, conduct and analysis minimized bias in the estimation of effectiveness. Quality items were assessed using existing texts and checklists. 15 A study was considered as of good quality if it used a prospective randomized study design, pro- vided evidence of adequate allocation concealment at randomization, if groups were comparable at baseline, follow-up was greater than 80%, sample size estimation was reported, the target population was clearly described and if intention to treat analysis was performed. A score out of 7 was given to each study, with a higher score indicating higher quality. Data synthesis Data, including number of patients, mean and standard deviation were extracted from all includ- ed papers. Values were analyzed by student’s two- sample t-tests, to get mean difference, 95% confidence intervals and p-values. Pain scores measured by visual analog scales (VAS) were Chapter 8 107 standardized to a 0-10 continuous scale. All statistical analyses were performed using Review Manager 5 (version 5, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration 2008).

A total of 107 citations were identified by electronic searches (Figure 1). After detailed evalua- tion of the papers, 13 articles appeared to meet the selection criteria. Upon closer inspection, nine papers had to be excluded for the following reasons: duplicate publication, study not ran- domized,16 intervention not of interest,17 type of intervention used was unclear 18 and population not of interest (these papers focused on dysmenorrhea rather than idiopathic CPP).19-21 This left three trials, (which were described in four papers) meeting the selection criteria for the review.22-25 Figure 1 Study selection process for systematic review of Psychological therapies for Chronic Pelvic Pain *Haugstad et al described results at baseline and 90 days post treatment in their 2006 paper (22), while their 2008 paper disseminated findings 12 months post treatment (23). Both articles are describing the same trial. Total citations identified from electronic searches n = 107 Citations excluded after screening titles/ abstracts n = 94 Articles retrieved for detailed evaluation n = 13 Articles excluded: n = 9 • Duplicate n = 3 • Study design not of interest n = 1 • Intervention not of interest n = 1 • Intervention unclear n = 1 • Disease group not of interest n = 3 Articles included in systematic review n = 4 (reporting 3 trials) * Systematic Review of Psychological Therapies for CPP 108 There was considerable variation in the type of psychological intervention. One trial assessed the value of additional Mensendieck somatocognitive therapy, which helps train specific muscle groups in defined movement patterns, compared with standard gynecological treatment and reported outcomes at 3 and 12 months.22,23 This intervention fulfils our definition of psychological therapy, as it also encourages body awareness and cognitions about pain through reflection. The second study assessed the effect of seeing a photograph of the internal pelvic organs taken dur- ing diagnostic laparoscopy in the post-operative consultation.24 The final trial compared behavio- ral counseling, non-directive counseling or relaxation techniques with verbal reassurance after a laparoscopic diagnosis of idiopathic CPP . 25 This study specifically targeted the pain experienced by patients, who were asked to report pain free days rather than rate their pain as scores on the VAS. The three active interventions in this study were delivered by a psychologist. The compara- tive effectiveness of the interventions from the three different studies could not be quantitated due to clinical heterogeneity and inconsistent reporting of pain severity. Table 1 provides a summary of the characteristics of trials included in the systematic review and a breakdown of their study quality. Quality of the included studies was generally adequate. All stud- ies were prospective, although not all reported concealment of allocation. Sample sizes in two tri- als 23,25 were small, as a valid sample size was not calculated a priori. The small sample size of the Pearce et al study25 also meant that their power to detect any modest but clinically meaningful difference between the treatments was almost nil. Blinding of participants is not usually possible in participatory psychological interventions, although, the study of Mensendieck somatocognitive therapy22 measured outcomes such as motor function using a blinded assessor. Patient reported pain Two studies provided VAS pain scores. 23,24 Figure 2 shows a forest plot of these studies, where randomized groups were classified as psychological intervention versus none. VAS pain scores were reported at 3 months in both trials but then at either 6 or 12 months post-randomization, so were grouped as 6 months or greater. At 3 months the mean difference in pain score was -3.27 (95% CI -4.52 to -2.02) and 1.11 (95% CI -0.05 to 2.27), whereas at 6 months or greater the values were -3.95 (95% CI -5.35 to -2.55) and 0.54 (95% CI -0.78 to 1.86). Chapter 8 109 Figure 2 Forest plot showing pain scores at the end of follow-up for studies included in the systematic review of Psychological therapies for Chronic Pelvic Pain * IV – Inverse variance The trial of Mensendieck therapy 22 used a blinded, standardized performance score of five do- mains (posture, gait, movement, sitting posture and respiration) on a scale of 0 - 7. At 3 months of treatment, a statistically significant difference was observed only in the sitting posture (mean difference -0.93, 95%CI -1.77 to -0.09; p=0.03) and respiration (mean difference -1.37, 95%CI -2.24 to -0.50, p=0.003) in favor of the additional Mensendieck therapy. The final study25 the only one using a ‘true’ psychological intervention, used the poor pain meas- ure of the number of pain free days in the month prior to treatment and during months 3 and twelve. At three months, an increase of 8, 12 and 10 pain free days from baseline was observed with the relaxation, non-directive counseling and behavioral counseling groups, respectively. The control group was not assessed at 3 months or baseline and the number of pain free days was unbalanced, so the comparative effectiveness of the three approaches cannot be judged.

Our review, demonstrates the scant nature of evidence on the use of psychological therapies for treating idiopathic CPP . The current evidence does not allow us to conclude whether psycholog- ical interventions have an effect on self reported pain scores in women with CPP . Mensendieck somatocognitive therapy assessed through a good quality trial 22 had a favorable effect when used in addition to standard gynecological treatment. This therapeutic approach can be seen as a hybrid between physiotherapy and psychotherapy26, and involves teaching patients how to change their posture, breathing patterns and the way they move in order to reduce their pain. It uses a cognitive approach to lead women to an improved understanding and experience of their own body. The second study hypothesized that photograph reinforcement in the post-operative consultation might reduce reported pain, but whether this approach can be formally defined as Stud y 1.1.1 Psychological intervention vs No psycholgical intervention - 3 months Haugstad 2006 Onwude 2004 1.1.2 Psychological intervention vs No psychological intervention - 6 months and greater Haugstad 2008 Onwude 2004 Mea n 2.8 9 4.3 4 2 3.7 6 S D 1.7 3 3.4 3 1.5 7 3. 5 Tota l 1 9 5 8 1 8 4 5 Mea n 6.1 6 3.2 3 5.9 5 3.2 2 S D 2.1 7 2.9 7 2.6 6 3.2 1 Tota l 1 9 6 0 1 9 5 7 Weigh t Inverse Variance, Random Effects, 95% CI -3.27 [-4.52, - 2.02] 1.11 [-0.05, 2.27] -3.95 [-5.35, - 2.55] 0.54 [-0.78, 1.86] Interventio n Contro l Mean Difference Mean Difference Inverse Variance, Random effects, 95% CI - 10 - 5 0 5 1 0 Favours intervention Favours control Systematic Review of Psychological Therapies for CPP 110 “psychological therapy” is debatable. It is possible that there could be an element of reassur - ance for patients in being shown a picture of their abdomen, but further exploration of how the patient interprets presence and absence of visual pathology, in the context of the diagnosis, is warranted27. Although several reviews discussing the management of CPP using psychotherapy exist, to our knowledge this is the first systematic review of randomized controlled trials of psychological therapies in women with idiopathic CPP . Quality of the included studies varied, with the oldest study failing to report an adequate randomization method and incurring >20% loss of data at follow-up28. The small size of the studies increased the chance of a type 2 error. However one trial23 showed a positive result beyond the play of chance. Our diverse results can be attributed to the heterogeneous studies identified and included in our review, as there were no common interventions or outcomes, limiting the clinical impact of our findings. The need for more robust studies, involving women with CPP receiving an established form of psychological therapy in which pain is measured as a continuous outcome, is obvious. Future trials should also consider the recommendations of the IMMPACT initiative and employ outcome measures that not only capture the intensity of pain, but the effect on physical and emotional functioning29. Future trials should have larger numbers 30,31, aiming to recruit 350 or more patients to detect a more realistic, but worthwhile, effect of any psychological intervention. To explore when the benefit emerges and whether it is maintained, longer follow-up of participants is recommended. In chronic conditions where outcomes may vary over time, repeated measures analyses will maximize statistical power from the trial sample. An ideal trial would involve cognitive behavioral therapy (CBT), since this is the mainstay of psychological treatment for CPP . Furthermore, there is evidence that this form of therapy has a small effect on pain, pain behavior and mood when used to treat other types of pain 32,33.

We would like to thank Derick Yates, clinical librarian from Birmingham Womens Hospital NHS Trust, for carrying out the literature searches on our behalf. Chapter 8 111 Table 1 Table of characteristics of studies included in the systematic review of Psychological therapies for Chronic Pelvic Pain Paper Population Sample size Intervention Comparator Outcome measures Study quality Haugstad et al 2006 (22) (1 year follow-up given in Haugstad 2008) (23) Women with chronic pelvic pain unexplained by pelvic pathology 40 Standard gynecological treatment + Somato- cognitive therapy (Mensendieck somatocognitive therapy) Standard gynecological treatment Reduction in physical pain, by changing posture, movement and respiration patterns, measured using mensendieck test of motor function (posture, movement, gait, sitting posture and respiration) and a visual analogue score of pain obtained before and after the 90 day treatment period - Prospective randomized study design: Yes - Adequate allocation concealment: Yes - Populations comparable at baseline: Yes - Follow-up > 80%: Yes - Appropriate sample size calculation done: No - Target population clearly described: Yes - Intention to treat analysis done: Yes TOTAL: 6/7 Onwude et al 2004 (24) Women undergoing diagnostic laparoscopy for the investigation of chronic pelvic pain 233 Being shown a Polaroid photograph of their pelvis Not being shown a Polaroid photograph of their pelvis Pain severity and pain belief scores at 3 and 6 months. - Prospective randomized study design: Yes - Adequate allocation concealment: Yes - Populations comparable at baseline: Yes - Follow-up >80%: Yes - Appropriate sample size calculation done: Yes - Target population clearly described: Yes - Intention to treat analysis done: Yes TOTAL: 7/7 Pearce et al 1982 (25) Women who attended a gynecological outpatient clinic, complaining of chronic pelvic pain of at least 6 months’ duration. 32 Women were randomized to either: 1. Behavioral counseling 2. Non-directive counseling 3. Relaxation Verbal reassurance Effectiveness of treatments for treating pelvic pain of non-organic origin - Prospective randomized study design: Yes - Adequate allocation concealment: Not stated - Populations comparable at baseline: Yes - Follow-up >80%: No - Appropriate sample size calculation done: No - Target population clearly described: Yes - Intention to treat analysis done: Yes TOTAL: 4/7 Systematic Review of Psychological Therapies for CPP 112

1 Latthe P , Latthe M, Say L, Gulmezoglu M, Khan KS. WHO systematic review of prev- alence of chronic pelvic pain: a neglected reproductive health morbidity. BMC Public Health 2006;6:177-93. 2 Vercellini P , Fedele L, Arcani L, Bianchi S, Rognoni MT, Candiani GB. Laparoscopy in the diagnosis of chronic pelvic pain in adolescent women. J Reprod Med 1989;34(10):827- 30. 3 Jamieson DJ, Steege JF. The prevalence of dysmenorrhoea, dyspareunia, pelvic pain and irritable bowel syndrome in primary care practices. Obstet Gynecol 1996;87:332-7. 4 Moen M, Schei B. Epidemiology of endometriosis in a Norwegian county. Acta Obstet Gynecol Scand 1997;76:559-62. 5 Stones RW, Mountfield J. Interventions for treating chronic pelvic pain in women. Cochrane Database of Systematic Reviews 2003;4. 6 Zondervan KT, Yudkin PL, Vessey MP , Jenkinson CP , Dawes MG, Barlow DH, et al. Chronic pelvic pain in the community - symptoms, investigations, and diagnoses. Am Obstet Gynecol 2001;184:1149-55. 7 Aslam N, Harrison G, Khan K, Patwardhan S. Visceral hyperalgesia in chronic pelvic pain. BJOG 2009;116(12):1551-5. 8 Daniels JP , Khan KS. Chronic Pelvic Pain in women. BMJ 2010;341:c4834. 9 Latthe P , Mignini L, Gray R, Hills R, Khan K. Factors predisposing women to chronic pel- vic pain: systematic review. BMJ 2006;332(7544):749-55. 10 Proctor ML, Murphy PA, Pattison HM, Suckling J, Farquhar CM. Behavioural interventions for primary and secondary dysmenorrhea. Cochrane Database of Systematic Reviews 2007;3. 11 Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Qual- ity of Reporting of Meta-analyses. Lancet 1999;354(9193):1896-900. 12 Khan KS, Kunz R, Kleijnen J, Antes G. Systematic reviews to support evidence-based medicine. How to review and apply findings of healthcare research. 2nd ed. 2003. Royal Society of Medicine Press Limited, London, UK 13 Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6(7):e1000097. 14 British Psychological Society Centre for Outcomes Research and Effectiveness., Depart- ment of Health. Treatment choice in Psychological therapies and counselling - Evidence based clinical practice guideline. 2001. Report No.: 23044. www.doh.gov.uk/en/publica- tionsandstatistics/publications/Pubilcationspolicyandguidance/DH_4007323 Chapter 8 113 15 Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommenda- tions for improving the quality of reports of parallel-group randomised trials. Lancet 2001;357(9263):1191-4. 16 Albert H. Psychosomatic group treatment helps women with chronic pelvic pain. J Psy- chosomatic Obstet Gynaecol 1999;20:216-25. 17 Heyman J, Ohrvik J, Leppert J. Distension of painful structures in the treatment for chron- ic pelvic pain in women. Acta Obstet Gynecol Scand 2006;85(5):599-603. 18 Peters AAW, van Dorst E, Jellis B, van Zuuren E, Hermans J, Trimbos JB. A randomised clinical trial to compare two different approaches in women with chronic pelvic pain. Ob- stet Gynecol 1991;77:740-4. 19 Amodei N, Nelson RO, Jarrett RB, Sigmon S. Psychological treatments of dysmenorrhea: Differential effectiveness for spasmodics and congestives. J Behavior Ther Experim Psy- chiatry 1987;18(2):95-103. 20 Chesney MA, Tasto DL. The effectiveness of behavior modification with spasmodic and congestive dysmenorrhea. Behaviour Res Ther 1975;13:245-53. 21 Quillen MA. Self-control of dysmenorrheic symptoms through pain management training. J Behavior Ther Experim Psychiatry 1982;13(2):123-30. 22 Haugstad GK, Haugstad TS, Kirste UM, Leganger S, Klemmetsen I, Malt UF. Mensendieck somatocognitive therapy as treatment approach to chronic pelvic pain: Results of a ran- domised controlled intervention study. Am Obstet Gynecol 2006;194:1303-10. 23 Haugstad GK, Haugstad TS, Kirste UM, Leganger S, Wojniusz S, Klemmetsen I, et al. Continuing improvement of chronic pelvic pain in women after short-term Mensendieck somatocognitive therapy: results of a 1-year follow-up study. Am Obstet Gynecol 2008;199(6):615.e1-615.e8. 24 Onwude JL, Thornton JG, Morley S, Lilleyman J, Currie I, Lilford RJ. A randomised trial of photographic reinforcement during postoperative counselling after diagnostic laparos- copy for pelvic pain. Eur Obstet Gynecol Reprod Biol 2004;112(1):89-94. 25 Pearce S, Knight C, Beard RW. Pelvic Pain - A common gynaecological problem. J Psy- chosomatic Obstet Gynaecol 1982;1:12-7. 26 Haugstad GK, Kirste U, Leganger S, Haakonsen E, Haugstad TS. Somatocognitive therapy in the management of chronic gynaecological pain. A review of the historical background and results of a current approach. Scandinavian Journal of Pain 2011;2:124-9. 27 Linton SJ, McCracken LM, Vlaeyen JWS. Reassurance: Help or hinder in the treatment of pain. Pain 2008;134:5-8. 28 Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assess- ing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 1996;17(1):1-12. Systematic Review of Psychological Therapies for CPP 114 29 Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, et al. Core outcomes measures for chronic pain clinical trials: IMMPACT guidelines. Pain 2005;113:9-19. 30 Hills RK, Daniels JP . Assessing new interventions in women’s health. Best Pract Res Clin Obstet Gynaecol 2006;20(5):713-28. 31 Khan KS, Selman T, Daniels J. Gynecology Randomized Control Trials. Handbook of Clinical Trials. Wiley and Sons, Inc. Hoboken, New Jersey, USA; 2009. p. 519-30. Editor: Shayne Cox Gad 32 Bernardy K, Fuber N, Kollner V, Hauser W. Efficacy of cognitive-behavioral therapies in fibromyalgia syndrome - a systematic review and metaanalysis of randomized controlled trials. J Rheumatol 2010;37(10):1991-2005. 33 Johnson RE, Jones GT, Wiles NJ, Chaddock C, Potter RG, Roberts C, et al. Active exer- cise, education, and cognitive behavioral therapy for persistent disabling low back pain: a randomized controlled trial. Spine 2007;32(15):1578-85. Chapter 8 115 Systematic Review of Psychological Therapies for CPP 116 117 Chapter 9 Hysterectomy, endometrial destruction and Mirena® for heavy menstrual bleeding: A systematic review and individual patient data meta-analysis 118 Chapter 9

Objective: Heavy menstrual bleeding is a common condition that does not always respond to oral medication. We undertook an individual patient data (IPD) meta-analysis to evaluate the rela- tive effectiveness of hysterectomy, endometrial destruction (both ‘first generation’ hysteroscopic and ‘second generation’ non-hysteroscopic techniques) and Mirena® (levonorgestrel releasing intrauterine system).

Individual patient data on 2814 women were available from 17 of the 30 randomised controlled trials identified (14 trials including 2448 women for first versus second generation endometrial destruction; 7 trials including 1127 women for hysterectomy versus first generation endometrial destruction; 5 trials including 304 women for second generation endometrial de- struction versus Mirena@; 3 trials including 190 women for first generation endometrial destruc- tion versus Mirena@; 1 trial including 236 women for hysterectomy versus Mirena @). Direct and indirect comparisons were made where appropriate to assess the effect of interventions on the primary outcome measure of patient dissatisfaction.

At around 12 months, 7.3% (12.6% v 5.3%) more women were dissatisfied with out- come of first generation hysteroscopic techniques than hysterectomy (OR [Odds Ratio]:2.46, 95%CI 1.54 to 3.93, p=0.0002), but hospital stay (WMD [Weighted Mean Difference]:3.0 days, 95%CI 2.9 to 3.1, p<0.00001) and time to resumption of normal activities (WMD:5.2 days, 95%CI 4.7 to 5.7, p<0.00001) were longer for hysterectomy. Unsatisfactory outcomes were comparable with first and second generation techniques (OR:1.20, 95%CI 0.88 to 1.62, p=0.2), although second generation techniques were quicker (WMD:14.5 minutes, 95%CI 13.7 to 15.3, p<0.00001) and women recovered sooner (WMD:0.48 days, 95%CI 0.20 to 0.75, p=0.0008) with fewer procedural complications. Indirect comparison suggested more unsatisfactory out- comes with second generation techniques than hysterectomy (10.6% v 5.3%; OR:2.32, 95%CI 1.27 to 4.24, p=0.006).

More women are dissatisfied following endometrial destruction than hysterectomy. However, dissatisfaction rates are low after all treatments and hysterectomy is associated with increased hospital stay and recovery period. Definitive evidence on effectiveness of Mirena ® compared to more invasive procedures is lacking.

Endometrial destruction, hysterectomy, heavy menstrual bleeding, menorrhagia, Mirena® Chapter 9 119

Heavy menstrual bleeding (HMB) is a common problem among women of reproductive age 1. It is often incapacitating, expensive to treat and significantly impacts on women’s quality of life2,3. Many women are not happy with medical treatment and end up undergoing surgery 4. Hyster- ectomy was once the only surgical option for HMB, and indeed, almost half of the hysterecto- mies currently performed worldwide are for the treatment of HMB5. Endometrial destruction (ED) techniques, which aim to destroy or remove the endometrial tissue 6 have become increasingly popular alternatives and, as a result, the number of hysterectomies in the UK has declined by 64% between 1995 and 2002 7. ED techniques were introduced in the 1980’s, with rollerball ablation and transcervical resection emerging as the predominant approaches under direct hyst- eroscopic vision 8. Subsequently, there have been a development of a second generation of non- hysteroscopic techniques which are easier to perform. Here, endometrial destruction is achieved through a variety of modalities, including high temperature fluids, bipolar electrical, or microwave energy. Intrauterine coil devices were initially introduced as contraceptives, but the addition of progestogen resulted in reduced menstrual bleeding. Mirena ®, a levonorgesterol releasing intrau- terine system provides a non-surgical alternative, which is reversible and fertility sparing9. Women and clinicians now have greater choice of treatment, although evidence to support deci- sion making is inadequate. In the UK, guidelines from the National Institute of Healthcare and Clinical Excellence 10 recommend the use of Mirena ® in the first instance for women with be- nign HMB, followed by ED if pharmaceutical treatments fail to resolve symptoms. Syntheses of evidence from randomised controlled trials (RCTs) comparing these treatments have been limited11-13, partly due to scarcity of head-to-head comparisons and variation in outcome meas- urements used to evaluate effectiveness. We undertook a meta-analysis of individual patient data (IPD) from all relevant trials, to address previous deficiencies in evidence synthesis. IPD meta- analysis has a number of advantages over traditional published data reviews14, including the abil- ity to carry out data checks, standardise analytical methods and undertake subgroup analyses.

We sought IPD from RCTs of hysterectomy, ED techniques and Mirena ® to examine their rela- tive efficacy as second line treatment of HMB. The systematic review was conducted based on a protocol designed using widely recommended methods 15,16 that complied with meta-analysis reporting guidelines17 (http://www.bctu.bham.ac.uk/systematicreview/hmb/protocol.shtml). Literature search and study selection The Cochrane Library, Medline (1966-2008), Embase (1980 to July 2008) and CINAHL data- bases (1982 to July 2008) were searched using relevant terms and word variants for population HMB IPD Meta-analysis 120 and interventions. We also hand-searched the bibliographies of all relevant primary articles and reviews, to identify any articles missed by the electronic searches. Experts were contacted to identify further studies. To identify any ongoing RCTs, the Meta-Register of Controlled Trials and the ISRCTN register were searched. No language restriction was applied. Studies were selected in a two step process. Firstly we scrutinised the citations identified by the electronic searches and obtained full manuscripts of all the citations that met, or were thought likely to meet, the predetermined inclusion criteria based on patient entry criteria (women with HMB or abnormal/excessive/prolonged uterine bleeding that was unresponsive to other medical treatment) and study design, the latter limited to RCTs only. We then considered four catego- ries of intervention: Hysterectomy (performed abdominally, vaginally or laparoscopically); ‘first generation’ ED techniques (using operative hysteroscopy, including endometrial laser ablation, transcervical resection of the endometrium (TCRE) and rollerball endometrial ablation); ‘second generation’ ED techniques (including thermal balloon (Cavaterm ®, Thermachoice® and Vesta®), microwave (Microsulis®), laser (ELITT ®), bipolar radio frequency (NovaSure ®), cryoablation and hydrothermal ablation); and levonorgesterol releasing intrauterine system (Mirena®). Our intention was to compare these categories of treatment against each other; studies were not included in the meta-analysis if a comparison between relevant categories did not exist. Data from studies making a comparison within these categories were also requested to allow further exploration of possible predictors of the primary outcome measure. Data collection and study quality assessment Repeated attempts were made to contact corresponding authors via post, email or telephone to access data. Where initial attempts failed, we attempted personal contact via our links through the British and European Societies for Gynaecological Endoscopy. Authors were asked to supply anonymised data for each of the pre-specified outcome measures and were invited to become part of the collaborative group with joint ownership of the final publication. Where the investiga- tors declined to take part in the study or could not be contacted, published data were extracted from manuscripts using pre-designed pro-formas by two independent reviewers (RC and LJM). Any disagreements were resolved by consensus or arbitration by a third reviewer (JPD). Received data were merged into a master database, specifically constructed for the IPD meta-analysis. The data were cleaned and results cross-checked against published reports of the trials. Where discrepancies existed authors were contacted for clarification. Patient dissatisfaction was used as the primary outcome measure. Level of satisfaction was the most frequently measured outcome, but dissatisfaction was used here to simplify interpreta- tion of statistical output. Responses were dichotomised, with an “unsure” or “dissatisfied” re- sponse interpreted as indicative of an unsatisfactory rating of treatment. Perception of treatment Chapter 9 121 (“moderate”/”poor”), recommendation to a friend (“not sure”/”not recommended”), or resolution of the major presenting problem (“no”) were used as substitutes if dissatisfaction was not report- ed explicitly, however not all trials could contribute to this end-point as a suitable measure was not always available. Ideally, a more disease specific quality of life tool would have been used 18, but the majority of studies did not employ such a measure. Other outcome measures were bleeding scores (ranging from a minimum of 0 with no upper limit)19, amenorrhoea rate (converted from a bleeding score of 0 where data existed, otherwise as reported), HMB rate (converted from bleeding scores of >10019 where data existed, otherwise as reported), EQ-5D utility score 20, SF-36 scores 21, duration of surgery/hospital stay, general anaesthesia rates, post-operative pain score (standardised onto a 0-10 scale), time to return to work/normal activities/sexual activity, dysmenorrhoea/dyspareunia rate and proportion undergo- ing subsequent ablation/hysterectomy or discontinuing use of Mirena ®. Pre-defined subgroups were age at randomisation (≤40 v >40 years), parity (nulliparous v parous), uterine cavity length (≤8 v >8 cm), presence or absence of fibroids/polyps and, where available, severity of bleeding at baseline (bleeding score≤350 or >350). Time points up to 2 years were considered; results from the limited number of studies with longer term follow-up are given in the Data Supplement but are not referred to in detail. Data at less than 12 months were combined, and are described as results at 6 months. All selected trials were assessed for their methodological quality, using received datasets where available in addition to the reported information. Quality was scrutinised by checking adequacy of randomisation, group comparability at baseline (examining baseline characteristics for any substantive differences), blinding (where appropriate), use of intention-to-treat (ITT) analysis, completeness of follow-up, compliance, reliability using a priori sample size estimation and gen- eralisability using description of the sample recruited. Adequacy of randomisation was assessed with sub-questions examining information on sequence generation, the process of allocation, and allocation concealment. Statistical analysis To minimise the possibility of bias IPD and aggregate data (AD) were combined in a two-stage approach 22. IPD were reduced to AD to allow studies with AD only to be combined with those where IPD were obtained. Point estimates and 95% confidence intervals (CI) were calculated for individual studies at each time point. Differences in effect estimates between trials and the pre- defined subgroups of patients are displayed using odds ratio plots, with heterogeneity investigat- ed using Cochran’s Q Statistic23. Sensitivity analyses to explore the causes of heterogeneity were undertaken if the p-values of these tests were <0.1. Differences between studies contributing IPD and those with AD only were examined in the same fashion to check that the latter results were HMB IPD Meta-analysis 122 consistent with those we received IPD for. Further details are given in the results section if any inconsistency exists. Likewise, further details are given on any obvious publication bias if noted from the assessment of funnel plots. Only a limited amount of data were available for studies comparing Mirena® with ED, so Mirena@ was compared with first and second generation studies combined as well as separately. Assumption free ‘fixed effect’ methods were used to combine dichotomous outcome measures and estimate pooled odds ratios (OR) using the method of Peto24, and, for continuous variables, weighted mean differences (WMD) were calculated 25 at each time point. The primary outcome measure of dissatisfaction was investigated comprehensively using re- ceived data. Results at 12 months, where the majority of studies had collected data, were used as the focus for analysis. Where responses were not available at this time point data were sub- stituted, in the first instance from 2 years and failing that 6 months. If it was not possible to make a direct comparison between treatments (e.g. hysterectomy vs second generation ED), indirect estimates were made26 using a logistic regression model27 allowing for trial and treatment28. Es- timates using dissatisfaction at any time were also examined, along with an analysis allowing for the correlation of the repeated measurements using generalised estimating equations (IPD only) 29. Access to IPD also allowed the inclusion of patient-level covariates to examine possible predic- tors of dissatisfaction. First, covariates were considered individually, whilst allowing for differ - ences between trial estimates. If considered statistically important (p<0.1), covariate parameters were included together in a multivariate analysis to examine adjusted estimates. In addition to the analysis of the primary outcome measure described above, as a sensitivity analysis, IPD were also used to explore the effect observed in compliance rates for comparisons between first and second generation ED (unfortunately there were insufficient data to extend this analysis to Mirena @ comparisons). For example, for those women ‘satisfied’ with treatment but subsequently undergoing a hysterectomy, positive responses were substituted with negative ones. Revman v5.0 (Cochrane Collaboration, Denmark) and SAS v9.2 (SAS Institute, Cary, USA) software were used for analysis.

Trials and patients A total of 556 potentially relevant citations were identified by electronic searches. After detailed evaluation, 30 trials were eligible for inclusion in the review (Figure 1). Of these trials, seven compared hysterectomy with ED techniques. Six of these studies involved first generation tech- niques 30-35. The seventh study used a combination of first and second generation in equal pro- Chapter 9 123 portions36 and was included here as a first generation comparison, with a sensitivity analysis performed without the trial. One study compared hysterectomy37 with Mirena®. Fourteen studies compared first generation ED techniques with those of second generation38-51 and eight studies compared Mirena® with ED, three of which were first generation 52-54 and five second genera- tion55-59. Characteristics of these studies are shown in the Data Supplement. Data from a further five studies60-64, which involved comparisons within first and second generation ED, were also received. Trials comparing hysterectomy with ED and those comparing first and second generation ED involved women of a similar age, with averages of 40.6 years (95%CI 40.3 to 40.9) and 41.0 years (95%CI 40.8 to 41.2), respectively. Women involved in trials comparing Mirena ® with ED were slightly older, with an average age of 43.6 years (95%CI 43.3 to 44.0). Eligibility criteria for women with uterine pathology varied between trials; inclusion of women with fibroids was gen- erally limited by size or number. Where included, they amounted to a maximum of 30% of the women in each individual study. A high proportion of data was received from trials involving hysterectomy (7/8 studies, 1278 of 1363 women), less for trials of ED techniques (7/14 studies, 1359 of 2448 women) and those involving Mirena ® (3/8 studies, 177 of 494 women). Overall, we received some IPD from 65% (2814/4305) of women involved in the trials, although only 8 studies were able to provide all requested variables31,32,38,39,42,45,51,59. The remaining studies had some missing information, with limited details on patient follow-up covering subsequent operations (e.g. hysterectomy following Mirena ®). See section on statistical analysis for details on how data from studies providing IPD was utilised. Study quality The methodological quality of the published data from the studies was variable (Figure 2, ). Over half the studies failed to give adequate information about their randomisation procedure and de- tails on allocation concealment. There was a general lack of true ITT analysis, with some studies stating that an ITT had been performed yet only analysing those women that had received treat- ment. For 4 studies that reported non-ITT analyses39,42,45,57 ITT analyses were undertaken using the available IPD, although it was not always clear if protocol deviant patients were followed-up correctly in these cases. Small sample sizes often lacked a sensible justification, especially in studies involving Mirena ®. In the nine trials involving Mirena @, only four had greater than 80% of women with Mirena® in situ at 12 months post-randomisation. HMB IPD Meta-analysis 124 Figure 1 Study selection process for systematic review and individual patient data (IPD) meta- analysis of randomised trials comparing hysterectomy, ED techniques and Mirena® for HMB Satisfaction as an outcome within 2 years (with IPD) Articles retrieved for detailed evaluation (n=111) Total citations identified (n=557) Articles included (n=39) Articles included in systematic review and meta-analysis (n=40) Unpublished studies (n=1*) Articles excluded (n=72): Abstract/letter (n=6) Data not extractable (n=9) Duplicates (n=57) Trials unable to contribute to meta-analysis (n=10): First generation v first generation (n=4) Second generation v second generation (n=4) Hysterectomy v hysterectomy (n=2) Mirena v first generation endometrial destruction (n=3; 190 women) Mirena v second generation endometrial destruction (n=5; 304 women) First v second generation endometrial destruction (n=14; 2448 women) Hysterectomy v Mirena (n=1; 236 women) Hysterectomy v first generation endometrial destruction (n=7; 1127 women) No IPD obtained (0 women) IPD obtained from 3 trials (177 women) IPD obtained from 7 trials (1359 women) IPD obtained from 1 trial (236 women) IPD obtained from 6 trials (1042 women) 0 1 trial (83 women)6 trials (1083 women)03 trials (570 women) Chapter 9 125 Figure 2 Quality of studies included in systematic review and individual patient data (IPD) meta- analysis of randomised trials comparing hysterectomy, ED techniques and Mirena ® for HMB. Numbers inside bars are numbers of studies. Effectiveness in reducing dissatisfaction with treatment Hysterectomy versus first generation endometrial destruction More women were dissatisfied at 12 months following first generation ED than hysterectomy (12.6% vs 5.3%; OR:2.46, 95%CI 1.54 to 3.93, p=0.0002) (Figure 3), with no significant het- erogeneity between study estimates (p=0.9). This estimate of effect size was consistent with, although slightly less, than the estimate from the repeated measures analysis (IPD only) over all time points (OR:3.75, 95%CI 2.18-6.46, p<0.0001) and an analysis using dissatisfaction at any time point (OR:3.37, 95%CI 2.14-5.31, p<0.0001). There was no evidence of any differences be- Ablation, Mirena® and Hysterectomy for Heavy Menstrual Bleeding 31 Figure 2: Quality of studies included in systematic review and individual patient data (IPD) meta-analysis of randomised trials comparing hysterectomy, ED techniques and Mirena® for HMB. Numbers inside bars are numbers of studies (details given in appendix 3). HMB IPD Meta-analysis 126 tween subgroups (see data collection and study quality assessment section), including between studies providing IPD or AD (test for heterogeneity: p=0.9). Figure 3 Dissatisfaction at 12 months - Hysterectomy vs First Generation ED First versus second generation endometrial destruction techniques Similar dissatisfaction rates were seen with second and first generation ED (10.6% vs 12.2%; OR:1.20, 95%CI 0.88 to 1.62, p=0.2; test for heterogeneity: p=0.7) (Figure 4). Similar estimates were obtained from the repeated measures analysis of IPD (OR:1.21, 95%CI 0.84 to 1.74, p=0.3), the analysis using dissatisfaction at any time (OR:1.22, 95%CI 0.91 to 1.62, p=0.2) and also an analysis adjusting for patients who went onto receive hysterectomy (OR:1.25, 95%CI 0.93 to 1.67, p=0.1). Results were consistent over all subgroups, including those studies provid- ing IPD or AD only (test for heterogeneity p=0.8). Figure 4 Dissatisfaction at 12 months - First vs Second Generation ED Ablation, Mirena® and Hysterectomy for Heavy Menstrual Bleeding 32 Figure 3: Dissatisfaction at 12 months - Hysterectomy vs First Generation ED Ablation, Mirena® and Hysterectomy for Heavy Menstrual Bleeding 33 Figure 4: Dissatisfaction at 12 months - First vs Second Generation ED Chapter 9 127 Mirena® versus endometrial destruction techniques Rates of dissatisfaction with Mirena® and second generation ED were similar (18.1% vs 22.5%; OR:0.76, 95%CI 0.38 to 1.53, p=0.4) (Figure 5). The combined estimate of this and the one study which compared Mirena @ with first generation ED 54 (test for differences between sub- groups: p=0.2), also showed no evidence of a difference (OR:0.94, 95%CI 0.50 to 1.77, p=0.9; test for heterogeneity over all studies: p=0.1). Overall rates of dissatisfaction were 17.2% for Mirena @ and 18.2% for both first and second generation ED. Lack of IPD prohibited any further investigation of subgroups or repeated measures. Indirect comparisons of hysterectomy with second generation endometrial destruction tech- niques and Mirena@ Indirect estimates (Figure 6) suggest hysterectomy is also preferable to second generation ED (OR:2.32, 95%CI 1.27 to 4.24, p=0.006) in terms of patient dissatisfaction. This is confirmed by the repeated measures analysis over all 3 time points, which perforce only include IPD (OR:3.06, 95%CI 1.59 to 5.90, p=0.0008). The evidence to suggest hysterectomy is preferable to Mirena @ was weaker (OR:2.22, 95%CI:0.94-5.29, p=0.07), but given the lack of precision from Mirena @ comparisons this was not a surprising result. Figure 5 Dissatisfaction at 12 months – First and Second generation ED v Mirena@ Ablation, Mirena® and Hysterectomy for Heavy Menstrual Bleeding 34 Figure 5: Dissatisfaction at 12 months – First and Second generation ED v Mirena HMB IPD Meta-analysis 128 Figure 6 Dissatisfaction at 12 months summary. Estimates >1 indicate increased dissatisfac- tion for the second treatment listed. Indirect estimates are represented by a dotted line. Predictors of dissatisfaction For second generation ED, uterine cavity length was the strongest predictor of dissatisfaction (p=0.02), with shorter uterine cavity length (8cm) associated with reduced rates (OR: 0.59, 95%CI 0.38-0.93; p=0.02) (Table 1). Absence of fibroids/polyps also showed a trend to- wards reduced dissatisfaction (p=0.07), although no further adjusted estimates including both parameters were attempted as only 3 studies had data on fibroids/polyps. There were no con- vincing associations with any of the variables for hysterectomy or first generation ED. Effectiveness in improving other outcomes Hysterectomy versus endometrial destruction and Mirena ® These comparisons focused on recovery times and quality of life, as estimates of post operative menstrual blood loss are redundant after hysterectomy. ED offered quicker surgery (WMD:32 minutes, 95%CI 30 to 34, p<0.0001), shorter hospital stay (WMD:3.0 days, 95%CI 2.9 to 3.1, p<0.00001), faster recovery periods (time to return to normal activities: WMD:5.2 days, 95%CI 4.7 to 5.7, p<0.00001) and less pain post-operatively (WMD:2.5 points, 95%CI 2.2 to 2.9, p<0.0001), although estimates of differences for some of these parameters should be used with caution given high variability between studies. One study 36 suggested no obvious difference in EQ-5D utility score, whilst another35 suggested differences in favour of hysterectomy in the gen- eral health (WMD:9.6 points, 95%CI 5.7 to 13.5, p<0.0001), social functioning (WMD:24 points, 95%CI 21 to 27, p<0.0001) and vitality (WMD:13 points, 95%CI 9.3 to 16, p1 indicate increased dissatisfaction for the second treatment listed. Indirect estimates are represented by a dotted line. Chapter 9 129 of the SF-36 questionnaire. Peri-operative adverse events associated with hysterectomy were relatively few (each 0.5% to 2.0%) but urinary tract infections were more common with hysterec- tomy (43/530, 8.1%) than ED (9/585, 1.5%). Of the women who were initially treated with ED, 15% had undergone a hysterectomy by two years. Table 1 Results from logistic regression analysis with dissatisfaction at 12 months as the outcome Hysterectomy 1st generation ED 2nd generation ED OR (95% CI)# P-value OR (95% CI)# P-value OR (95% CI)# P-value Individual estimates*: Uterine cavity length (8) - - 0.97 (0.38-2.44) 0.9 0.59 (0.38-0.93) 0.02 Age (40) 2.28 (0.66- 7.89) 0.2 1.21 (0.81-1.81) 0.4 1.30 (0.87-1.93) 0.2 Fibroids/polyps (absence v presence) 0.51 (0.14- 1.93) 0.3 1.15 (0.55-2.38) 0.7 0.36 (0.12-1.07) 0.07 Parity (nullparous v parous) - - 1.27 (0.36-4.43) 0.7 0.84 (0.33-2.16) 0.7 Baseline bleeding score (<=350 v 350) - - 0.73 (0.27-1.97) 0.5 0.96 (0.48-1.91) 0.9 # Estimates <1 favour the first subgroup listed, i.e. have reduced dissatisfaction * after allowing for study No differences in EQ-5D scores were seen at 6 or 12 months in the single study comparing hysterectomy with Mirena®, whilst the only statistically significant effect observed in the SF-36 questionnaire was in the pain domain, favouring hysterectomy (WMD:9.6 points, 95%CI 2.7 to 16.6, p=0.007). All results were consistent over subgroups. First versus second generation endometrial destruction techniques The proportion of women with amenorrhoea or still experiencing HMB was similar in both groups at all time points apart from at 2 years, where there was a borderline significant difference in favour of 2nd generation techniques ([amenorrhea] OR:0.64, 95%CI 0.41 to 0.99, p=0.04; [HMB] OR:1.85, 95%CI 1.04 to 3.32, p=0.04). Change from baseline analysis of bleeding scores showed no evidence of a difference at any of the time points. Two studies 45,47 using the SF-36 questionnaire and one small study38 using the EQ-5D questionnaire showed no consistent differ- ence between first and second generation techniques. Second generation ED was quicker (WMD:15 minutes; 95%CI 14 to 15, p<0.0001), and less likely to need general anaesthesia (OR:0.16, 95%CI 0.12 to 0.20, p<0.0001), although highly significant heterogeneity makes estimates difficult to interpret. Lower use of general anaesthesia HMB IPD Meta-analysis 130 with second generation ED translated to a slightly quicker time to normal activities (WMD:0.48 days, 95%CI 0.20 to 0.75, p=0.0008) and time to return to work (WMD:1.36 days, 95%CI 0.69 to 2.03, p<0.0001). Post-operative pain was similar following either method of ED. Adverse events were relatively low in both groups (each <2%), but peri-operative complications such as uterine perforation, excessive bleeding, fluid overload and cervical laceration were higher with first generation ED. The number of women requiring a subsequent hysterectomy was lower for second generation ED, but these differences were not large enough to be statistically significant within the first two years ([1 year] OR:0.77, 95%CI 0.47 to 1.24, p=0.3; [2 years] OR:0.68, 95%CI 0.41 to 1.13, p=0.1). Overall rates were 3% (74/2265) and 8% (71/939) at these time points. Any differences amongst subgroups were confined to single time points only. Results from studies providing IPD were consistent with those with AD only. Mirena ® versus endometrial destruction techniques Fewer women experienced HMB after Mirena ® at 6 months (OR:0.23, 95%CI 0.09 to 0.57, p=0.001) and at 2 years (OR:0.08, 95%CI 0.01 to 0.50, p=0.007), although not at 12 months (OR:0.74, 95%CI 0.34 to 1.61, p=0.5), where most trials had made this measurement. Amenor- rhoea rates were similar at all time points. Change in bleeding scores favoured ED at 12 months only (WMD:38 points; 95%CI 15 to 60, p=0.0009). Other outcome measures could not separate the two treatments. Two studies 57,59 provided SF-36 change from baseline scores and no dif- ferences were found in any of the domains. The number of women subsequently undergoing a hysterectomy were similar at each time point; rates at 12 months were 2% (2/86) for ED and 7% (6/89) for Mirena @. A high proportion of women originally prescribed Mirena® discontinued use of this treatment: 30/191(16%) at 12 months, rising to 29/105 (28%) by 2 years. Reported adverse events were low with Mirena®; only around 3% reported an expelled/migrated coil within the first month. These results were from studies of first and second generation studies combined, where first generation data existed, and were consistent over both types of ED.

Main findings In this review, access to IPD enabled a more rigorous analysis than is possible from published data from trials comparing second line treatments for HMB. Based on direct and indirect com- parisons using all available data, the review found that both first and second generation ED techniques were associated with greater dissatisfaction than hysterectomy, although rates were low for all treatments and absolute differences were small. Recovery times and length of hospi- tal stay were longer for hysterectomy. Dissatisfaction levels with second generation techniques were slightly lower than those associated with first generation techniques. In addition, second generation methods of ED were quicker, had faster recovery times, were associated with fewer Chapter 9 131 adverse procedural events and could be offered under local anaesthetic. Less women subse- quently converted to hysterectomy after second generation ED compared with first generation ED, but this difference was not statistically significant. Shorter uterine cavity length showed was associated with lower levels of dissatisfaction for second generation ED. Comparisons of ED with Mirena ® suggest comparable efficacy, although trials were generally small and suffered from poor compliance in the Mirena@ arm. Strengths and limitations of the review We used optimal methodology, complying with guidelines on reporting of systematic reviews and meta-analyses 65. An extensive literature search was conducted, with no language restrictions, minimising the risk of missing information. The collection of IPD allowed us to use previously unreported data, to improve the assessment of study quality, to standardise outcome measures, undertake ITT analysis and use optimal analytical methods. Subgroup, repeated measures and multivariable analyses would not have been possible without the collection of IPD, and along with the indirect measures analysis, have not previously been reported. The review was hampered by the unavailability of IPD from at least 35% of randomised women, which could not be accessed as a number of trialists did not agree to collaborate or could not be contacted. Received data were sometimes incomplete and on occasions failed quality checks and so were unusable. The review’s inferences are also limited by the inconsistent outcome measure used across trials; studies involving ED and Mirena ® focused on comparing reduction in bleeding, whilst hysterectomy trials focused on patient satisfaction, quality of life and resource usage. Interpretation In this review we found that more women were dissatisfied following ED when compared to hysterectomy, although operating time, total hospital stay and recovery period are much less for ED. Nevertheless, rates of dissatisfaction are relatively low for ED and it is an effective alterna- tive to hysterectomy for women with abnormal uterine bleeding who do not seek amenorrhoea. Whilst this review has shown that hysterectomy is a relatively safe operation, other studies with a more comprehensive follow-up of large populations have shown higher levels of morbidity following hysterectomy 5. In contrast, ED has low rates of complication 66. All these factors need to be taken into consideration when considering any potential benefit of hysterectomy. Indeed, nearly fourteen women need to be treated with hysterectomy to prevent a single woman being dissatisfied with ED (number needed to treat from 1st generation comparison:13.7, 95%CI 9.1 to 28.4). Given the extra resources and recovery period needed for hysterectomy a benefit of this size may not be large enough to warrant its use. The cost-effectiveness of these treatments will be an important factor and this is to be examined separately in a concurrent study. HMB IPD Meta-analysis 132 We found that second generation techniques, such as thermal balloon ablation (Thermachoice® and Cavaterm®) 42,67,68, the Novasure® device44, or microwave (Microsulis®)47,69, were at least as effective as first generation techniques. Moreover, they are simpler and quicker, require less skill on the part of the operator and can be attempted under local anaesthetic. Importantly, fewer op- erative complications have also been recorded. Thus they are clearly preferable to first generation techniques. The association of shorter uterine cavity length and lower dissatisfaction with second generation ED could be because endoscopic treatment is technically more difficult, although given the borderline statistical significance it could also have arisen by chance. The comparisons involving Mirena® were encouraging and given that it is a relatively cheap and minimally invasive procedure, it could be considered first if drug treatment for heavy bleeding fails70. It may even be an alternative to drug treatment as a first line agent but we did not address this question in our review. However, research on Mirena® presents some difficulties in interpreta- tion, as seen in the trial by Hurskainen et al37, which compared Mirena® with hysterectomy. Whilst the study was well conducted and reported, the lack of further investigation into the analysis of the primary outcome measure (EQ-5D quality of life of life measure) made the interpretation of no evidence of a difference questionable. Of the women allocated Mirena ®, 20% had received hysterectomy before the main analysis time point at 12 months, with a further 12% no longer using the Mirena®. Unfortunately, missing IPD from this trial meant we could not examine further. Implications for practice Our review provides evidence that hysterectomy reduces dissatisfaction compared with ED and this information should be used as part of consultation with women making a choice about treat- ment options when initial drug treatment fails to control heavy menstrual bleeding. ED is satisfac- tory for a very high proportion of women, but, if complete cessation of bleeding is sought, then hysterectomy may be offered. Although the evidence is not strong, our findings concur with a recent NICE recommendation that women should be offered Mirena® before more invasive pro- cedures, particularly as this can be fitted in primary care10. Implications for research This review has shown that further investment in a randomised controlled trial comparing hyster- ectomy with second generation ED would be of limited value, given the similar efficacy of first and second generation techniques. Questions remain about the long term clinical effectiveness of all the treatments; evidence from trials with longer term follow-up (4/5 years or more) is limited to a handful of studies involving differing comparisons 36,37,71,72. Mirena®, in particular, versus alternative forms of surgical treatment requires further research. Whilst the small studies included in this review have indicated promising results for this treatment, the substantial levels of non-compliance makes interpretation of outcomes difficult and casts some doubt on the equivalent efficacy conclusions. Chapter 9 133 Individual patient data meta-analysis is an extremely powerful tool if used correctly73 and provides the most definitive possible synthesis of the available evidence. Such collaborative meta-analy- ses are well established in cancer and have greatly influenced clinical practice resulting in striking improvements in, for example, breast cancer survival 23. Clinicians in speciality groups, such as gynaecology, need to be aware that contributing study results to an IPD is certainly as important as conducting the original research if not more so. Consensus on optimal outcome measures would also be helpful for meta-analysis.

We would like to thank all authors of identified trials, for sending us their trial data, and both the British and European Societies of Gynaecological Endoscopy for their support and help with the review. Supplementary material Data supplements available at http://www.bmj.com/content/341/bmj.c3929 *Members of Collaborative group The following authors provided us with individual patient data from their trials (name, organisation, country): J Abbott, University of New South Wales, Sydney, Australia; J Barrington, Torbay Hospital, South Devon, UK; S Bhattacharya, University of Aberdeen, Aberdeen Maternity Hospital, Aberdeen, UK; M.Y. Bongers, Maxima Medical Centre, Veldhoven,The Netherlands; J-L Brun, Hopital Uni- versitarie Pellegrin, Bordeaux, France; R Busfield, data supplied by M Sowter, Auckland Obstet- ric Centre, New Zealand; T.J. Clark, Birmingham Womens Hospital, Birmingham, UK; J Cooper (2004 trial), data supplied by Microsulis Medical Ltd, Hampshire, UK; K.G. Cooper, Aberdeen Royal Infirmary, Aberdeen, UK; S.L. Corson (2001 trial), data supplied by Boston Scientific Cor- poration, Marlborough, USA; K Dickersin, John Hopkins Bloomberg School of Public Health, USA; N Dwyer, Weston General Hospital, Weston Super Mare, UK; M Gannon, Midland Regional Hospital, Mullingar, Ireland; J Hawe, Countess of Chester Hospital, Chester, UK; R. Hurskainen, University of Helsinki, Finland; W.R. Meyer; data supplied by Ethicon, A Johnson & Johnson Company, New Jersey, USA; H. O’Connor, Coombe Women’s Hospital, Dublin 8, Ireland; S. Pinion, Aberdeen Royal Infirmary, Aberdeen, UK; A.M. Sambrook, Aberdeen Royal Infirmary, Ab- erdeen, UK; W.H. Tam, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China; I.A.A. van Zon-Rabelink, Medical Spectrum Twente, Enschede, The Netherlands, E. Zupi, Tor Vergata University, Rome, Italy. HMB IPD Meta-analysis 134

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The statistical basis of meta-analysis. Statistical Methods in Medical research 1993;2:121-45. 26 Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D’Amico R et al. Indirect com- parisons of competing interventions. Health Technol Assess 2005 July;9(26):1-iv. 27 Hasselblad V. Meta-analysis of multitreatment studies. Med Decis Making 1998 Janu- ary;18(1):37-43. 28 Whitehead A. Meta-Analysis of Controlled Clinical Trials. Wiley, Chichester; 2002. 29 Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986 March;42(1):121-30. 30 Crosignani PG, Vercellini P , Apolone G, De Giorgi O, Cortesi I, Meschia M. Endometrial resection versus vaginal hysterectomy for menorrhagia: long-term clinical and quality-of- life outcomes. American Journal of Obstetrics and Gynecology 1997;177(1):95-101. 31 Dwyer N, Hutton J, Stirrat GM. Randomised controlled trial comparing endometrial re- section with abdominal hysterectomy for the surgical treatment of menorrhagia. British Journal of Obstetrics and Gynaecology 1993;100:237-43. 32 Gannon M, Holt EM, Fairbank J, Fitzgerald M, Milne MA, Crystal A.M. et al. A randomised control trial comparing endometrial resection and abdominal hysterectomy for the treat- ment of menorrhagia. BMJ 1991;303:1362-4. HMB IPD Meta-analysis 136 33 O’Connor H, Broadbent JA, Magos AL, McPherson K. Medical Research Council ran- domised trial of endometrial resection versus hysterectomy in the management of menor- rhagia. Lancet 1997;349(9056):891-901. 34 Pinion SB, Parkin DE, Abramovich DR, Naji A, Alexander DA, Russell IT. Randomised trial of hysterectomy, endometrial laser ablation, and transcervical endometrial resection for dysfunctional uterine bleeding. BMJ 1994;309(6960):979-83. 35 Zupi E, Zullo F, Marconi D, Sbracia M, Pellicano M, Solima E. et al. Hysteroscopic endome- trial resection versus laparoscopic supracervical hysterectomy for menorrhagia: a prospec- tive randomized trial. American Journal of Obstetrics and Gynecology 2003;188(1):7-12. 36 Dickersin K, Munro MG, Clark M, Langenberg P , Scherer R, Frick K. et al. Hysterectomy compared with endometrial ablation for dysfunctional uterine bleeding: a randomized controlled trial. Obstetrics and Gynecology 2007;110(6):1279-89. 37 Hurskainen R, Teperi J, Rissanen P , Aalto AM, Grenman S, Kivela A. Quality of life and cost-effectiveness of levonorgestrel-releasing intrauterine system versus hysterectomy for treatment of menorrhagia: a randomised trial. Lancet 2001;357(9252):273-7. 38 Hawe J, Abbott J, Hunter D, Phillips G, Garry R. A randomised controlled trial compar - ing the Cavaterm endometrial ablation system with the Nd:YAG laser for the treatment of dysfunctional uterine bleeding. BJOG 2003;110(4):350-7. 39 van Zon-Rabelink IA, Vleugels MPH, Merkus HMWM, de Graaf R. Efficacy and satisfac- tion rate comparing endometrial ablation by rollerball electrocoagulation to uterine bal- loon thermal ablation in a randomised controlled trial. Eur J Obstet Gynecol Reprod Biol 2004;114:97-103. 40 Soysal ME, Soysal SK, Vicdan K. Thermal balloon ablation in myoma-induced menorrhagia under local anesthesia. Gynecologic and obstetric investigation 2001;51(2):128-33. 41 Romer T. [Therapy of recurrent menorrhagia--Cavaterm balloon coagulation versus roller- ball endometrium coagulation--a prospective randomized comparative study]. Zentralbl Gynakol 1998;120(10):511-4. 42 Meyer WR, Walsh BW, Grainger DA, Peacock LM, Loffer FD, Steege JF. Thermal Balloon and rollerball ablation to treat menorrhagia: a multicenter comparison. Obstetrics and Gynecology 1998;92:98-103. 43 Duleba AJ, Heppard MC, Soderstrom RM, Townsend DE. A randomized study compar- ing endometrial cryoablation and rollerball electroablation for treatment of dysfunctional uterine bleeding. Journal of the American Association of Gynecologic Laparoscopists 2003;10(1):17-26. 44 Cooper J, Gimpelson R, Laberge P , Galen D, Garza-Leal JG, Scott J. A randomised, mul- ticenter trial of safety and efficacy of the NovaSure system in the treatment of menorrhagia. Journal of the American Association of Gynecologic Laparoscopists 2002;9(4):418-28. Chapter 9 137 45 Cooper J, Anderson TL, Fortin CA, Jack SA, Plentl M.B. Microwave endometrial ablation vs. rollerball electroablation for menorrhagia: a multicenter randomized trial. Journal of the American Association of Gynecologic Laparoscopists 2004;11(3):394-403. 46 Perino A, Castelli A, Cucinella G, Bionda A, Pane A, Venezia R. A randomized comparison of endometrial laser intrauterine thermotherapy and hysteroscopic endometrial resection. Fertility and Sterility 2004;82(3):731-4. 47 Cooper KG, Bain C, Parkin DE. Comparison of microwave endometrial ablation and tran- scervical resection of the endometrium for treatment of heavy menstrual loss: a ran- domised trial. Lancet 1999;354(9193):1859-63. 48 Corson SL, Brill AI, Brooks PG, Cooper JM, Indman PD, Liu JH. et al. One-year results of the vesta system for endometrial ablation. Journal of the American Association of Gy- necologic Laparoscopists 2000;7(4):489-97. 49 Corson SL. A multicenter evaluation of endometrial ablation by Hydro ThermAblator and rollerball for treatment of menorrhagia. Journal of the American Association of Gyneco- logic Laparoscopists 2001;8(3):359-67. 50 Pellicano M, Guida M, Acunzo G, Cirillo D, Bifulco G, Nappi C. Hysteroscopic transcer - vical endometrial resection versus thermal destruction for menorrhagia: a prospective randomized trial on satisfaction rate. American Journal of Obstetrics and Gynecology 2002;187(3):545-50. 51 Brun JL, Burlet G, Galand B, Quereux C, Bernard P . Cavaterm thermal balloon endometrial ablation versus hysteroscopic endometrial resection to treat menorrhagia: the French, mul- ticenter, randomized study. Journal of Minimally Invasive Gynecology 2006;13(5):424-30. 52 Malak KA. Management of menorrhagia with the levonorgestrel intrauterine system ver - sus endometrial resection. Gynaecological Surgery 2006;3(4):275-80. 53 Kittelsen N, Istre O. A randomized study comparing levonorgestrel intrauterine system (LNG IUS) and transcervical resection of the endometrium (TCRE) in the treatment of menorrhagia: preliminary results. Gynaecological Endoscopy 1998 April 9;7(2):61-5. 54 Crosignani PG, Vercellini P , Mosconi P , Oldani S, Cortesi I, De Giorgi O. Levonorgestrel- releasing intrauterine device versus hysteroscopic endometrial resection in the treatment of dysfunctional uterine bleeding. Obstetrics and Gynecology 1997;90(2):257-63. 55 Soysal M, Soysal S, Ozer S. A randomized controlled trial of levonorgestrel releasing IUD and thermal balloon ablation in the treatment of menorrhagia. Zentralbl Gynakol 2002 April;124(4):213-9. 56 Barrington JW, Arunkalaivanan AS, Abdel-Fattah M. Comparison between the levonorg- estrel intrauterine system (LNG-IUS) and thermal balloon ablation in the treatment of men- orrhagia. Eur J Obstet Gynecol Reprod Biol 2003 May 1;108(1):72-4. HMB IPD Meta-analysis 138 57 Busfield RA, Farquhar CM, Sowter MC, Lethaby A, Sprecher M, Yu Y et al. A randomised trial comparing the levonorgestrel intrauterine system and thermal balloon ablation for heavy menstrual bleeding. BJOG 2006 March;113(3):257-63. 58 Shaw RW, Symonds IM, Tamizian O, Chaplain J, Mukhopadhyay S. Randomised com- parative trial of thermal balloon ablation and levonorgestrel intrauterine system in patients with idiopathic menorrhagia. Aust N Z J Obstet Gynaecol 2007 August;47(4):335-40. 59 Tam WH, Yuen PM, Shan Ng DP , Leung PL, Lok IH, Rogers MS. Health Status Function after treatment with thermal balloon endometrial ablation and levnonorgestrel intrauterine system for idiopathic menorrhagia: A randomised study. Gynecology and Obstetric Inves- tigation 2006;62(2):84-8. 60 Abbott J, Hawe J, Hunter D, Garry R. A double-blind randomized trial comparing the Ca- vaterm and the NovaSure endometrial ablation systems for the treatment of dysfunctional uterine bleeding. Fertility and Sterility 2003;80(1):203-8. 61 Bhattacharya S, Cameron IM, Parkin DE, Abramovich DR, Mollison J, Pinion SB. et al. A pragmatic randomised comparison of transcervical resection of the endometrium with en- dometrial laser ablation for the treatment of menorrhagia. BJOG 1997;104(5):601-7. 62 Bongers MY, Bourdrez P , Mol BW, Heintz AP , Brolmann HA. Randomised controlled trial of bipolar radio-frequency endometrial ablation and balloon endometrial ablation. BJOG 2004;111(10):1095-102. 63 Clark TJ. A randomised controlled trial to conmpare the effectiveness of outpatient endo- metrial ablation techniques (NovaSure versus Thermachoice) in the treatment of menor- rhagia. Unpublished 2008. 64 Sambrook AS, Cooper KG, Campbell MK, Cook JA. Clinical outcomes from a randomised comparison of Microwave Endometrial Ablation with Thermal Balloon endometrial abla- tion for the treatment of heavy menstrual bleeding. BJOG 2009;116(8):1038-45. 65 Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Qual- ity of Reporting of Meta-analyses. Lancet 1999;354(9193):1896-900. 66 Overton C, Hargreaves J, Maresh M. A national survey of the complications of endome- trial destruction for menstrual disorders: the MISTLETOE study. Minimally Invasive Surgi- cal Techniques- Laser, EndoThermal or Endoresection. British Journal of Obstetrics and Gynaecology 1997;104(12):1351-9. 67 Loffer FD. Three-year comparison of thermal balloon and rollerball ablation in tretament of menorrhagia. Journal of the American Association of Gynecologic Laparoscopists 2001;8(1):48-54. 68 Loffer FD, Grainger D. Five-year follow-up of patients participating in a randomised trial of uterine balloon therapy versus rollerball ablation for treatment of menorrhagia. Journal of the American Association of Gynecologic Laparoscopists 2002;9(4):429-35. Chapter 9 139 69 Cooper KG, Bain C, Lawrie L, Parkin DE. A randomised comparison of microwave endo- metrial ablation with transcervical resection of the endometrium; follow up at a minimum of five years. British Journal of Obstetrics and Gynaecology 2005;112(4):470-5. 70 Brown PM, Farquhar CM, Lethaby A, Sadler LC, Johnson NP . Cost-effectiveness analysis of levonorgestrel intrauterine system and thermal balloon ablation for heavy menstrual bleeding. BJOG 2006;113:797-803. 71 Cooper KG, Jack SA, Parkin DE, Grant AM. Five-year follow up of women randomised to medical management or transcervical resection of the endometrium as treatment for heavy menses. British Journal of Obstetrics and Gynaecology 2001;108:1222-8. 72 Sambrook AM, Bain C, Parkin DE, Cooper KG. A randomised comparison of microwave endometrial ablation with transcervical resection of the endometrium: follow up at a mini- mum of 10 years. BJOG 2009 July;116(8):1033-7. 73 Stewart LA, Clarke MJ. Practical methodology of meta-analyses (overviews) using updated individual patient data. Cochrane Working Group. Stat Med 1995 October 15;14(19):2057-79. 74 Dickersin K, Munro M, Langenberg P , Scherer R, Frick KD, Weber AM. et al. Surgical Treatments Outcomes Project for Dysfunctional Uterine Bleeding (STOP-DUB): design and methods. Controlled Clinical Trials 2003;24:591-609. 75 Sculpher MJ, Dwyer N, Byford S, Stirrat GM. Randomised trial comparing hysterectomy and transcervical endometrial resection: effect on health related quality of life and costs two years after surgery. BJOG 1996;103:142-9. 76 Sculpher M. A cost-utility analysis of abdominal hysterectomy versus transcervical en- dometrial resection for the surgical treatment of menorrhagia. International Journal of Technology Assessment in Health Care 1998;14:302-19. 77 Halmesmaki K, Hurskainen R, Teperi J, Grenman S, Kivela A, Kujansuu E. et al. The effect of hysterectomy or levonorgestrel-releasing intrauterine system on sexual func- tioning among women with menorrhagia: a 5-year randomised controlled trial. BJOG 2007;114:563-8. 78 van Zon-Rabelink IA, Vleugels MP , Merkus HM, de Graaf R. Endometrial ablation by roller- ball electrocoagulation compared to uterine balloon thermal ablation. Technical and safety aspects. Eur J Obstet Gynecol Reprod Biol 2003;110(2):220-3. 79 Bain C, Cooper KG, Parkin DE. Microwave endometrial ablation versus endometrial re- section: a randomized controlled trial. Obstetrics and Gynecology 2002;99(6):983-7. 80 Rauramo I, Elo I, Istre O. Long-term treatment of menorrhagia with levonorgestrel intrauter- ine system versus endometrial resection. Obstetrics and Gynecology 2004;104:1341-21. HMB IPD Meta-analysis 140 141 Chapter 10 Second generation endometrial ablation techniques for heavy menstrual bleeding: network meta-analysis 142 Chapter 10

Objective: To determine the relative effectiveness of second generation ablation techniques in the treatment of heavy menstrual bleeding. Design: Network meta-analysis on the primary outcome measures of amenorrhoea, heavy bleeding, and patients’ dissatisfaction with treatment. Data sources: Nineteen randomised controlled trials (involving 3287 women) were identified through electronic searches of the Cochrane Library, Medline, Embase and PsycINFO databases from inception to April 2011. The reference lists of known relevant articles were searched for further articles. Two reviewers independently selected articles without language restrictions. Eligibility criteria for selecting studies: Randomised controlled trials involving second gen- eration endometrial destruction techniques for women with heavy menstrual bleeding unrespon- sive to medical treatment.

Of the three most commonly used techniques, network meta-analysis showed that bipolar radiofrequency and microwave ablation resulted in higher rates of amenorrhoea than thermal balloon ablation at around 12 months (odds ratio 2.51, 95% confidence interval 1.53 to 4.12, p<0.001; and 1.66, 95% CI 1.01 to 2.71, p=0.05, respectively), but there was no evidence of a convincing difference between the three techniques in the number of women dissatisfied with treatment or still experiencing heavy bleeding. Compared with bipolar radio frequency and microwave devices, an increased number of women still experienced heavy bleeding after free fluid ablation (2.19, 95% CI 1.07 to 4.50, p=0.03; and 2.91, 95% CI 1.23 to 6.88, p=0.02, re- spectively). Compared with radio frequency ablation, free fluid ablation was associated with re- duced rates of amenorrhoea (0.36, 95% CI 0.19 to 0.67, p=0.004) and increased rates of dissat- isfaction (4.79, 95% CI 1.07 to 21.5, p=0.04). Of the less commonly used devices, endometrial laser intrauterine thermotherapy was associated with increased rates of amenorrhoea compared with all the other devices, while cryoablation led to a reduced rate compared with bipolar radio frequency and microwave.

Bipolar radio frequency and microwave ablative devices are more effective than thermal balloon and free fluid ablation in the treatment of heavy menstrual bleeding with second generation endometrial ablation devices. Chapter 10 143

Heavy menstrual bleeding is a common incapacitating problem in women of reproductive age, 1 which can severely affect their quality of life.2,3 When medical treatments fail to provide adequate relief, surgical interventions, including hysterectomy or destruction of the endometrium, can be considered.4 Initially, rollerball ablation, transcervical resection, and laser ablation were the predominant endometrial destruction techniques performed under direct hysteroscopic vision. These led to a rapid decrease in the number of hysterectomies performed. 5 Over the past decade, a second generation of non-hysteroscopic techniques, which are safer, technically easier to perform, involve shorter hospital stays, and can be performed under local anaesthesia, have become dominant.6,7 These involve devices that are sited and activated to treat the whole endometrial cavity. Destruction is achieved through various methods, the most com- monly used 8 being high temperature fluids within a balloon (Thermachoice and Cavaterm) 9-11 or application of microwave (Microsulis)12,13 or bipolar radiofrequency electrical energy (Novasure).14 Less commonly used ablative techniques include free fluid at high temperature (Hydrotherma- blator), 15 endometrial laser intrauterine thermotherapy (ELITT), 16 and cryoablation (HerOption). 17 Other than free fluid thermal ablation, these are “blind” techniques. A recent meta-analysis of in- dividual patient data found that second generation techniques were at least as effective, in terms of patients’ dissatisfaction, as first generation techniques and, importantly, gave rise to fewer operative complications, were considerably quicker, and were less likely to need to be performed under general anaesthesia. 18 Thus they are clearly preferable to first generation techniques. When more than two treatments options are available, the use of network meta-analysis, which allows us to combine both direct and indirect estimates for treatment effects, has become in- creasingly common. 19,20 Randomised comparisons within trials are preserved and the main as- sumption—that there are no systematic differences between the trials that could bias the indirect measurements—is similar to those underlying any standard meta-analysis. There have been numerous randomised controlled trials comparing the different second genera- tion techniques with each other or with first generation devices, yet with the sheer number of potential comparisons there are gaps in direct evidence for efficacy of some techniques, while other comparisons have low statistical power because of the small numbers randomised. We carried out a network meta-analysis to assess the relative effectiveness of six second generation techniques to provide both users and recipients of these devices with an improved evidence base to inform their decision making. HMB Network Meta-analysis 144

The systematic review was conducted based on a protocol designed with widely recommended methods21,22 that complied with reporting guidelines for meta-analyses.23 Literature search and study selection We carried out an extensive literature search in the Cochrane Library, Medline, Embase, and Psy- cINFO from inception to April 2011. Our search term combinations consisted of MeSH subhead- ings, text words and word variations for “heavy menstrual bleeding,” and the various types of first and second generation endometrial destruction techniques. This search strategy was adapted to suit each database and was restricted to “humans” and “females”. Bibliographies of known relevant primary articles and reviews were searched by hand to identify articles missed by the electronic searches. Were also contacted experts in the specialty to uncover any grey literature. A comprehensive database was constructed with Reference Manager 12.0 to store all identified references. No language restriction was applied. Studies were selected in a two step process. Firstly, we scrutinised the citations identified by the electronic searches and subsequently obtained full manuscripts of citations that met or were thought to have met the predetermined inclusion criteria. We included studies if they recruited women with heavy, abnormal, excessive, or prolonged uterine bleeding that was unresponsive to initial medical treatment and the study design was a randomised controlled trial comparing endometrial ablation methods. Data collection and study quality assessment Two reviewers (LJM and RC) independently inspected all the manuscripts to determine if they met the above criteria. When possible we obtained individual patient data from the primary au- thor using methods described in the related meta-analysis. 18 When raw data were not available, two independent reviewers (RC and LJM) used predesigned forms to extract aggregate data from manuscripts. Any disagreements were resolved by consensus or arbitration by a third re- viewer (JPD). Outcome measures used to evaluate the treatments were those most commonly used across studies (Table 1): rate of amenorrhoea (converted from a pictorial bleeding assessment score of zero when these data existed, otherwise as reported), rate of heavy bleeding (likewise converted from a pictorial bleeding assessment score of >10024 when data existed, otherwise as reported), and rate of dissatisfaction with treatment (see related paper for a full description of how dissatis- faction was calculated). 18 We used data at 12 months (the most popular time point) as the focus for analysis or results at two years if 12 month data were not available. Chapter 10 145 Table 1: Characteristics of included trials and event rates for amenorrhoea, heavy bleeding and dissatisfaction for the systematic review and network meta-analysis of second generation endometrial destruction techniques for heavy menstrual bleeding. Primary author Year Primary outcome measure Second generation treatment device Manufacturer/Trade name Amenorrhoea rate Heavy bleeding rate Dissatisfaction rate 2nd generation 1st generation 2nd generation 1st generation 2nd generation 1st generation Studies comparing second generation treatments Clark31 2011 Amenorrhoea rate Bipolar radio frequency NovaSure 14/25 - 2/25 - 2/28 - Thermal balloon Thermachoice 6/26 - 6/26 - 6/32 - Penninx32 2010 Amenorrhoea rate Bipolar radio frequency NovaSure 35/75 - 8/75 - 1/75 - Free-fluid BEI Medical Systems 17/71 - 10/71 - 10/71 Sambrook33 2009 Satisfaction rate Microwave Microsulis 61/149 - 6/149 - 35/144 - Thermal balloon Thermachoice 51/134 - 7/134 - 31/134 - Bongers34 2004 Amenorrhoea rate Biploar radio frequency NovaSure 34/79 - 14/79 - 8/83 - Thermal balloon Thermachoice 3/38 - 7/38 - 8/43 - Abbott35 2003 Amenorrhoea rate Biploar radio frequency NovaSure 16/37 - 5/37 - 0/34 - Thermal balloon Cavaterm 2/17 - 0/17 - 1/15 - Studies comparing second generation treatments with first generation hysteroscopic devices Brun36 2006 Amenorrhoea rate Thermal balloon Cavaterm 11/30 5/17 2/30 2/17 2/21 3/16 Cooper37 2004 Heavy bleeding rate Microwave Microsulis 120/194 49/96 5/194 5/96 3/196 1/97 Perino16 2004 Amenorrhoea rate Laser ELITT 35/56 14/55 2/56 4/55 3/56 5/55 Duleba17 2003 Heavy bleeding rate Cryoablation HerOption 43/156 40/72 19/156 5/72 16/156 10/72 Hawe38 2003 Amenorrhoea rate Thermal balloon Cavaterm 10/30 13/28 1/30 1/28 2/30 1/28 Van Zon- Rabelink39 2003 Heavy bleeding rate Thermal balloon Thermachoice 6/74 4/55 23/74 19/55 15/75* 13/58* Cooper14 2002 Heavy bleeding rate Biploar radio frequency NovaSure 63/154 29/82 14/154 10/82 11/154 5/82 Pellicano40 2002 Satisfaction rate Thermal balloon Cavaterm nm nm nm nm 7/37 14/38 Corson15 2001 Heavy bleeding rate Free-fluid BEI Medical Systems 65/172 43/83 31/172 12/83 nm nm Soysal41 2001 Heavy bleeding rate Thermal balloon Thermachoice 5/45 8/48 11/45 10/48 15/45 19/48 Corson42 2000 Heavy bleeding rate Thermal balloon Vesta 38/122 39/112 16/122 19/112 nm nm Cooper12 1999 Satisfaction rate Microwave Microsulis 46/116 48/124 9/116 11/124 27/116 32/124 Meyer9 1998 Heavy bleeding rate Thermal balloon Thermachoice 18/122 32/117 18/122 13/117 5/122 1/116 Romer43 1998 Not stated Thermal balloon Cavaterm 4/10 3/10 0/10 0/10 nm nm nm - outcome not measured * – indicates data from 24 months post-randomisation but considered as 12 month data. All other data are follow-up data at 12 months post-randomisation. HMB Network Meta-analysis 146 Statistical analysis For all three outcomes we first assessed direct estimates in individual trials by calculating point estimates and 95% confidence intervals. We then calculated a traditional weighted average me- ta-analysis yielding a Mantel-Haenszel odds ratio, with heterogeneity investigated with Cochran’s Q 25 and I2 statistics.26 We carried out the network meta-analysis by fitting a linear mixed model to the log odds ratio from each trial with the GLIMMIX procedure in SAS, using maximum likelihood to estimate treat- ment effects. Two models were attempted; the first included a fixed treatment effect and allowed the effect of the study to vary randomly. The second model also included a random effect for the difference in treatment in each trial by including a study by treatment interaction parameter. 27 The inclusion of a random study effect allowed the recovery of any differences between trials, which has greater importance when not all of the treatments are included in every trial, as is the case here. 28 We also included a random effect for treatment pair (that is, to separate those trials comparing different treatments types) in both models to allow for any inconsistency or “incoher- ence” in the model.29 This effect (ω, the standard deviation of the random effect) allows for any indirect estimates to be inconsistent with any direct estimates of the same treatments and can be calculated where there any closed “loops” of treatments exist (for instance, A v B, B v C, A v C). Increased incoherence increases standard errors, and hence the size of the confidence interval, of differences between treatments. If large levels of incoherence are present it might not be sen- sible to combine estimates with this method, 30 analogous to having high levels of heterogeneity in a standard meta-analysis. We used Revman v5.0 (Cochrane Collaboration, Denmark) and SAS v9.2 (SAS Institute, Cary, NC) software for analysis.

Trials and patients We identified 719 citations through the electronic literature searches (Figure 1) and excluded 672 after screening titles and abstracts. A further 28 were excluded for being duplicate publications or not involving direct comparisons of endometrial ablative techniques. After detailed evaluation of the citations, 19 primary articles met the selection criteria and were included in the network meta-analysis (see Supplementary data for full details of these 19 studies). These consisted of five head to head comparisons of second generation devices31-35 (744 women) and 14 compar- ing a second generation device with a first generation (hysteroscopic) device 9,12,14-17,36-43 (2543 women) (Figure 1). Table 1 shows further descriptions of device type and the frequencies used in the analysis. As the fixed and random effect network meta-analysis models produced similar

only those from the latter are described here. Chapter 10 147 Figure 1 Study selection process for systematic review and network meta-analysis of second generation endometrial destruction techniques for heavy menstrual bleeding. Figure 2 Network of studies evaluating second generation endometrial destruction devices for treatment of heavy menstrual bleeding. Number of women randomised to second generation treatment are shown in parentheses. Citations identi/f_ied by electronic searches (n=/seven.tf/one.tf/nine.tf) Citations retrieved for detailed evaluation (n=/four.tf/seven.tf) Articles included in systematic review and meta-analysis (n=/one.tf/nine.tf) Trials comparing second generation devices with /f_irst generation (hysteroscopic) devices (n=/one.tf/four.tf, /two.tf/five.tf/four.tf/three.tf women) Trials comparing two second generation devices (n=/five.tf, /seven.tf/four.tf/four.tf women) Citations excluded a/f_ter screening titles and abstracts (n=/six.tf/seven.tf/two.tf) Excluded (n=/two.tf/eight.tf): Duplication (n=/two.tf/two.tf) Inappropriate comparator (n=/six.tf) First generation hysteroscopic deviceFree fluid One study /three.tf/two.tf (n=/one.tf/six.tf/zero.tf) Bipolar radio frequency Three studies /three.tf/one.tf /three.tf/four.tf /three.tf/five.tf (n=/two.tf/six.tf/four.tf) Thermal balloon One study /three.tf/three.tf (n=/three.tf/two.tf/zero.tf) Microwave Laser Cryoablation One study /one.tf/four.tf (n=/one.tf/seven.tf/five.tf) Eight studies /nine.tf /three.tf/six.tf /three.tf/eight.tf-/four.tf/three.tf (n=/five.tf/one.tf/eight.tf) Two studies /one.tf/two.tf /three.tf/seven.tf (n=/three.tf/three.tf/eight.tf) One study /one.tf/six.tf (n=/five.tf/six.tf) One study /one.tf/seven.tf (n=/one.tf/nine.tf/three.tf) One study /one.tf/five.tf (n=/one.tf/eight.tf/seven.tf) HMB Network Meta-analysis 148 Effectiveness in reducing bleeding Direct comparisons show an increased rate of amenorrhoea with bipolar radio frequency ablation compared with thermal balloon ablation (odds ratio 4.56, 95% confidence interval 2.24 to 9.26; p<0.001) (Table 2). Free fluid thermal ablation was associated with reduced rates of amenorrhoea (0.36, 95% CI 0.18 to 0.73; p=0.005) and increased rates of heavy bleeding (4.88, 95% CI 1.32 to 18.11; p=0.02, Table 3) compared with bipolar radio frequency ablation. We found no other convincing differences. When there was more than one study in a comparison, estimates be- tween studies were highly consistent (all I 2=0% apart from the comparison of amenorrhoea rates with microwave ablation versus first generation techniques where I2=17%).

from the network meta-analysis (Tables 2 and 3 and Figure 3) concurred with the results of the direct evidence, with an increased rate of amenorrhea with bipolar radio frequency abla- tion compared with thermal balloon ablation (2.51, 95% CI 1.53 to 4.12; p<0.001). Results were also similar for the comparison between free fluid thermal ablation and bipolar radio frequency ablation for amenorrhoea (0.36, 95% CI 0.19 to 0.67; p=0.004) and heavy bleeding (2.19, 95% CI 1.07 to 4.50; p=0.03). There was an increase in the rate of amenorrhoea with radio frequency ablation compared with cryoablation in the indirect comparison (0.20, 95% CI 0.09 to 0.49; p=0.002). Microwave ablation was associated with an increased rate of amenorrhoea compared with thermal balloon ablation (1.66, 95% CI 1.01 to 2.71; p=0.05) and cryoablation (0.31, 95% CI 0.13 to 0.74; p=0.01) and some reduction in the rate of heavy bleeding compared with free fluid ablation (2.91, 1.23 to 6.88; P=0.02). The endometrial laser intrauterine thermotherapy (ELITT) was associated with increased rates amenorrhoea compared with all the other devices, with wide confidence intervals reflecting the small number of women evaluated with this device in ran- domised controlled trials (Table 2). No other compelling differences between devices were noted. There were relatively low but variable rates of heavy bleeding across the studies (such as 0-32% for thermal balloon ablation and 8-18% for bipolar radiofrequency ablation). Chapter 10 149 Table 2 Amenorrhoea rate at 12 months - results from direct comparisons and network meta-analysis Thermal balloon Bipolar radio frequency Microwave Cryoablation Free-fluid Laser First generation device Direct 0.72 (0.52,1.01); p=0.06a 1.27 (0.73,2.20); p=0.4c 1.28 (0.90,1.83); p=0.2b 0.30 (0.17,0.55); p<0.0001c 0.57 (0.33,0.96); p=0.03c 4.88 (2.17,11.00); p=0.0001c Network 0.69 (0.49,0.97); p=0.03 1.73 (1.07,2.78); p=0.03 1.14 (0.73,1.79); p=0.5 0.35 (0.17,0.75); p=0.01 0.62 (0.34,1.13); p=0.1 4.36 (1.82,10.44); p=0.002 Thermal balloon Direct 4.56 (2.24,9.26); p<0.0001a 1.13 (0.70,1.82); p=0.6c Not available Not available Not available Network 2.51 (1.53,4.12); p=0.0009 1.66 (1.01,2.71); p=0.05 0.51 (0.23,1.17); p=0.1 0.91 (0.48,1.73); p=0.7 6.34 (2.50,16.07); p=0.0004 Bipolar radio frequency Direct Not available Not available 0.36 (0.18,0.73); p=0.005c Not available Network 0.66 (0.36,1.21); p=0.2 0.20 (0.09,0.49); p=0.002 0.36 (0.19,0.67); p=0.004 2.52 (0.95,6.71); p=0.06 Microwave Direct Not available Not available Not available Network 0.31 (0.13,0.74); p=0.01 0.55 (0.27,1.13); p=0.09 3.82 (1.46,10.01); p=0.009 Cryoablation Direct Not available Not available Network 1.77 (0.69,4.58); p=0.2 12.37 (3.96,38.59); p=0.0002 Free-fluid Direct Not available Network 6.98 (2.48,19.69); p=0.0008 Figures are odds ratios (95% confidence intervals) for device in column compared with device in row. Odds ratio >1 indicate increased rate with device in column. a I2=0%, b I2 =17%, c I2 not applicable, only one study in comparison. HMB Network Meta-analysis 150 Table 3 Heavy bleeding rate at 12 months - results from direct comparisons and network meta-analysis Thermal balloon Bipolar radio frequency Microwave Cryoablation Free-fluid Laser First generation device Direct 0.97 (0.66,1.41); p=0.9a 0.72 (0.30,1.70); p=0.5b 0.71 (0.34,1.50); p=0.4a 1.86 (0.67,5.19); p=0.2b 1.30 (0.63,2.69); p=0.5b 0.47 (0.08,2.69); p=0.4b Network 0.98 (0.69,1.39); p=0.9 0.95 (0.56,1.62); p=0.8 0.59 (0.32,1.09); p=0.09 1.55 (0.63,3.81); p=0.3 1.37 (0.74,2.51); p=0.3 0.39 (0.07,2.09); p=0.3 Thermal balloon Direct 1.02 (0.46,2.29); p=1.0a 0.76 (0.25,2.32); p=0.6b Not available Not available Not available Network 0.82 (0.47,1.44); p=0.5 0.62 (0.32,1.18); p=0.1 1.62 (0.62,4.24); p=0.3 1.80 (0.90,3.57); p=0.09 0.41 (0.07,2.27); p=0.3 Bipolar radio frequency Direct Not available Not available 4.88 (1.32,18.11); p=0.02b Not available Network 0.75 (0.34,1.66); p=0.5 1.98 (0.70,5.60); p=0.2 2.19 (1.07,4.50); p=0.03 0.50 (0.09,2.89); p=0.4 Microwave Direct Not available Not available Not available Network 2.63 (0.89,7.78); p=0.08 2.91 (1.23,6.88); p=0.02 0.66 (0.11,3.96); p=0.6 Cryoablation Direct Not available Not available Network 1.11 (0.37,3.29); p=0.9 0.25 (0.04,1.70); p=0.2 Free-fluid Direct Not available Network 0.23 (0.04,1.36); p=0.1 Figures are odds ratios (95% confidence intervals) for device in column compared with device in row. Odds ratio >1 indicate increased rate with device in column. a I2 0% b I2 not applicable, only one study in comparison. Chapter 10 151 Figure 3 Amenorrhoea rate at 12 months from network meta-analysis (odds ratio and 95% confidence intervals). Results reflect those in Table 2 (*indicates reversed ratios so all are pointing in direction of increased amenorrhoea rate). Only results with p≤0.05 are shown. Effectiveness in reducing dissatisfaction with treatment Direct comparisons showed some evidence of reduced rates of dissatisfaction with bipolar radio frequency ablation compared with thermal balloon ablation (0.39, 95% CI 0.16 to 0.91; p=0.03) (Table 4), though this difference was not as convincing in the network meta-analysis (0.56, 95% CI 0.28 to 1.09; p=0.09). Increased dissatisfaction was seen with free fluid thermal ablation com- pared with bipolar radio frequency (9.40, 95% CI 1.14 to 77.18; p=0.04) and a similar result was seen in the network meta-analysis (4.79, 95% CI 1.07 to 21.48; p=0.04). There were no other obvious differences. Direct estimates between studies were also consistent for dissatisfaction where more than one study in a comparison existed (0%<I 2<4%). Overall rates of dissatisfaction were generally low (such as 0-7% for bipolar radiofrequency ablation). MicrowaveCryoablation LaserBipolar radio frequency Thermal balloonFree fluid /three.tf./two.tf/three.tf (/one.tf./three.tf/six.tf to /seven.tf./seven.tf/one.tf)* /one.tf./six.tf/six.tf (/one.tf./zero.tf/one.tf to /two.tf./seven.tf/one.tf) /one.tf/two.tf./three.tf/seven.tf (/three.tf./nine.tf/six.tf to /three.tf/eight.tf./five.tf/nine.tf) /six.tf./nine.tf/eight.tf (/two.tf./four.tf/eight.tf to /one.tf/nine.tf./six.tf/nine.tf) /two.tf./five.tf/one.tf (/one.tf./five.tf/three.tf to /four.tf./one.tf/two.tf) /four.tf./nine.tf/one.tf (/two.tf./zero.tf/four.tf to /one.tf/one.tf./eight.tf/zero.tf)* /two.tf./seven.tf/seven.tf (/one.tf./four.tf/nine.tf to /five.tf./one.tf/four.tf)* /three.tf./eight.tf/two.tf (/one.tf./four.tf/six.tf to /one.tf/zero.tf./zero.tf/one.tf) /six.tf./three.tf/four.tf (/two.tf./five.tf/zero.tf to /one.tf/six.tf./zero.tf/seven.tf) HMB Network Meta-analysis 152 Table 4: Dissatisfaction rate at 12 months - results from direct comparisons and network meta-analysis. Thermal balloon Bipolar radio frequency Microwave Cryoablation Free-fluid Laser First generation device Direct 0.80 (0.50, 1.27); p=0.3b 1.18 (0.40,3.53); p=0.8c 0.90 (0.51,1.60); p=0.7a 0.71 (0.30,1.65); p=0.4c Not available 0.57 (0.13,2.49); p=0.5c Network 0.91 (0.61,1.36); p=0.6 0.51 (0.25,1.01); p=0.05 0.93 (0.59,1.47); p=0.7 0.93 (0.59,1.47); p=0.7 3.14 (0.66,14.83); p=0.1 0.54 (0.12,2.43) p=0.4 Thermal balloon Direct 0.39 (0.16,0.91); p=0.03a 1.07 (0.61,1.86); p=0.8c Not available Not available Not available Network 0.56 (0.28,1.09); p=0.09 1.02 (0.65,1.60); p=0.9 0.79 (0.31,2.05); p=0.6 2.66 (0.55,12.96); p=0.2 0.59 (0.12,2.78); p=0.5 Bipolar radio frequency Direct Not available Not available 9.40 (1.14,77.18); p=0.04c Not available Network 1.83 (0.85,3.95); p=0.1 1.42 (0.47,4.29); p=0.5 4.79 (1.07,21.48); p=0.04 1.06 (0.20,5.51); p=0.9 Microwave Direct Not available Not available Not available Network 0.78 (0.29,2.07); p=0.6 2.62 (0.52,13.23); p=0.2 0.58 (0.12,2.79); p=0.5 Cryoablation Direct Not available Not available Network 3.37 (0.56,20.39); p=0.2 0.74 (0.13,4.25); p=0.7 Free-fluid Direct Not available Network 0.22 (0.03,1.95); p=0.2 The device in the column is compared to the device in the row. Increased dissatisfaction rate with column device is indicated by OR>1 (for example: increased rate with free-fluid compared to bipolar radio frequency). Odds ratios, 95% confidence intervals and p-values shown. a I2=0%, b I2 =4%, c I2 n/a Incoherence Estimates of incoherence, ω, from the network model of amenorrhoea rate were relatively high at 0.23 compared with other studies that have used this technique to evaluate multiple treatments simultaneously. 19,30,44 When we removed the single trial comparing microwave ablation with ther- mal balloon ablation,33 this estimate was reduced to 0.13. This trial’s direct estimate yielded no significant difference between treatments (1.13, 95% CI 0.70 to 1.82; p=0.6), which conflicted Chapter 10 153 with the estimate expected by any indirect comparison where the network analysis favoured microwave ablation (1.66, 95% CI 1.01 to 2.71; p=0.05). A sensitivity analysis of the network analysis with this trial excluded produced a higher estimate in favour of microwave ablation (2.23, 95% CI 1.21 to 4.09; p=0.02), with some other minor adjustments to the other estimates (free fluid ablation was now associated with a lower amenorrhoea rate also compared with microwave ablation: 0.45, 95% CI 0.21 to 0.97; p=0.04). Incoherence parameters for heavy bleeding and dissatisfaction, along with the interaction parameter for study by treatment, were estimated to be so close to zero that they were negligible and so effectively did not contribute to any estimates.

Main findings Of the three most popular second generation endometrial ablation devices (thermal balloon, bipolar radio frequency, and microwave) examined in this network meta-analysis, bipolar radio frequency and microwave ablation techniques seem to have an advantage over thermal balloon ablation in terms of increased amenorrhea rate in women with heavy menstrual bleeding. Com- pared with free fluid ablation, both bipolar radio frequency and microwave ablation techniques were associated with a reduction in the number of women still experiencing heavy bleeding. Ra- dio frequency ablation was also associated with an increased amenorrhoea rate and a reduced number of women dissatisfied with treatment compared with free fluid ablation. Endometrial laser intrauterine thermotherapy (ELITT) was also associated with high rates of amenorrhoea compared with hysteroscopic ablation in the small single study that evaluated this technique. Not surprisingly this translated to estimates of amenorrhoea higher than the other devices when we combined results in the network meta-analysis. Conversely, cryoablation was associated with lower rates of amenorrhoea compared with bipolar radio frequency and microwave ablative techniques. Rates of dissatisfaction with treatment or ongoing heavy bleeding were generally low across all studies. Apart from the comparison of microwave ablation versus thermal balloon abla- tion, estimates from the network meta-analysis were consistent with available direct estimates between second generation devices in terms of direction and significance of treatment effect. The implication of this inconsistency from this one comparison is unclear. Strengths and limitations of the review We used the relatively new approach of network meta-analysis to synthesise data, and this pro- vided effect estimates when direct comparisons were not available. We used optimal methods, complying with guidelines on reporting of systematic reviews and meta-analyses. 23 We carried out an extensive literature search, with no language restrictions, minimising the risk of missing information. The collection of individual patient data from some studies improved estimates. The review was not intended to be a comprehensive review of all facets of these devices, and we focused only on outcomes of bleeding after treatment reported by patients and patients’ dissat- HMB Network Meta-analysis 154 isfaction with treatment. Many other factors, such as ease of use and safety of device, are taken into account in the decision regarding a particular device. For example, the time to complete treatment is significantly shorter with bipolar radiofrequency ablation, and it results in greater coverage of the endometrial surface than thermal balloon ablation, in an out-patient setting.31 Because of the limited amount of data (several comparisons consisted of only one trial) and the fact that the traditional meta-analysis did not show any evidence of heterogeneity between esti- mates (I 2 was generally 0% and never greater than 17%) we did not attempt to further subgroup

by manufacturer or type (Thermachoice, Cavaterm, and the discontinued Vesta all are types of thermal balloon ablative device). This consistency could have occurred by chance, and there could be some differences because of the design of similar products. This could be reason- ably evaluated only should more data become available. We considered that the first generation ablative techniques of transcervical endometrial resection and rollerball electrocoagulation were equivalent so we used them as a generic intermediate comparator. 45,46 Estimates of incoherence were relatively high for the analysis of amenorrhoea rate (less when we omitted one of the studies in a sensitivity analysis), though how this impacts on adjusted esti- mates is debatable, given that confidence intervals of estimates were increased as a result. Like all meta-analysis, we must consider limitations with combining estimates from different studies because of clinical heterogeneity such as differences in populations of patients, even with statisti- cal adjustments in the analysis. For example, the small study that compared endometrial laser intrauterine thermotherapy (ELITT) with first generation techniques seemed to show a large treat- ment effect. Given that none of the other studies has shown a comparable effect, there could be something particular about this study, such as the lower rate of amenorrhoea for the first genera- tion comparator, that separates it from the rest, but in the absence of raw data, we were unable to investigate this further. Conversely, the absence of a significant difference does not necessarily mean that techniques are comparable but could be a consequence of small underpowered trial populations. This is reflected in wide confidence intervals for some of the estimates. We did not take into account quality of study in these analyses; the only requirement was that the study needed to be randomised in a specified population of patients. The usefulness of the network meta-analysis in this setting was highlighted during the course of this review when we updated the analysis to include the results of the most recent study of bipolar radio frequency and free fluid endometrial ablation 32; the first to compare these two treatments di- rectly. Results from this study for the primary outcome measure of amenorrhoea rate at 12 months suggested improvements with radio frequency, with an odds ratio of 0.36 (0.17 to 0.73). Before inclusion of this later study, our original estimated odds ratio from the network meta-analysis was 0.33, which is similar albeit with a slightly wider confidence interval (0.11 to 0.98). Such an accurate estimate could of course occur by chance, but it does show how useful this analytical method could be where direct head to head assessments of treatments are not available. Chapter 10 155 Interpretation Rates of dissatisfaction and heavy bleeding are consistently low for second generation tech- niques, which, as a group, represent an excellent conservative alternative to hysterectomy. It is clear from the results of our review that bipolar radiofrequency and microwave ablation technique are associated with higher amenorrhea rates than other methods, although it should be reiterat- ed that only hysterectomy can guarantee complete cessation of menstrual bleeding. Endometrial laser intrauterine thermotherapy (ELITT) was associated with highly significant improvements in amenorrhea rates compared with all other methods, albeit from one small study, but this device is no longer marketed (C Dunn, Karl Storz, personal communication). Data from UK hospital episode statistics show a significant increase in the overall number of inpatient endometrial ablative techniques (Figure 4), though radiofrequency ablation techniques are recently the most rapidly rising techniques used. These data do not include ambulatory pro- cedures, which are also increasing rapidly but not adequately coded in the hospital episode data. More recently, the microwave endometrial ablation system from Microsulis has been withdrawn from the European market after Hologic acquired the intellectual property for the device (Micro- sulis Medical, press release, 2011). Ambiguous categorisation of first generation techniques in the episode data precludes comparison of relative rates, but consensus is that such techniques have rapidly been superseded. Figure 4 Trends in types of endometrial ablation procedures performed in England, 2004-11 (data from hospital episode statistics) Years No of inpatient procedures performed in England (000s) /two.tf/zero.tf/zero.tf/four.tf-/five.tf /two.tf/zero.tf/zero.tf/five.tf-/six.tf /two.tf/zero.tf/zero.tf/six.tf-/seven.tf /two.tf/zero.tf/zero.tf/seven.tf-/eight.tf /two.tf/zero.tf/zero.tf/eight.tf-/nine.tf /two.tf/zero.tf/zero.tf/one.tf/zero.tf-/one.tf/one.tf/two.tf/zero.tf/zero.tf/nine.tf-/one.tf/zero.tf /zero.tf /one.tf /two.tf /three.tf /four.tf /six.tf /five.tf Thermal balloon Endometrial ablation Microwave Free fluid Bipolar radio frequency HMB Network Meta-analysis 156 With respect to costs and cost effectiveness, one study has directly compared thermal balloon and microwave ablative techniques.47 The mean total health service cost per patient was £181 (£70 to £434) more (equivalent to about €219, $287) for the thermal balloon system than for the microwave ablative device (at 2010 costs), though the study found no significant differences between the total non-health costs and health benefits of the two devices. The incremental cost effectiveness ratio showed microwave ablation, on average, dominated thermal balloon ablation at one year after the procedure. Our previous review indicated that levels of dissatisfaction with second generation techniques, as a class of procedure, were slightly lower than those associated with first generation tech- niques. Second generation techniques were also quicker, associated with faster recovery times and fewer adverse procedural events, and could be carried out under local anaesthesia. 18 Thus they should be offered when no structural or histological abnormality is present and the woman wants to retain her uterus. While chances of pregnancy are reduced after endometrial ablation, they can occur and such pregnancies have a high risk of adverse outcomes, hence continued contraception is strongly advised.48 As to the question of the best second generation technique, bipolar radiofrequency ablation seems to offer benefits over thermal balloon in terms of amenorrhea rates and is procedurally quicker than thermal balloon and microwave ablation.31,33-35 Any impact on other outcomes was not significant in either direct comparisons or network meta-analysis. Only two studies have evaluated the use of these three devices under local anaesthesia, 31,33 so while out-patient hyster- oscopic treatment is feasible, it would be premature to state any advantage for either anaesthetic approach. The decision should be left to the women’s preference and the operator’s experience, though the withdrawal of the microwave ablation device reduces available choices. Further large scale rigorous randomised trials to compare existing and emerging ablative tech- niques should use meaningful and standardised measures of satisfaction and menstrual bleeding and be run independently from the manufacturers of the devices. Trials incorporating different anaesthetic approaches will also help to refine the evidence available to women and gynaecolo- gists. Concerns with regard to the safety of the “blind” techniques with respect to extrauterine injury should lead to further evaluation of visual ablative techniques such as the next generation of free fluid ablation. Adequate assessment of relatively rare adverse events, however, would require large cohorts similar to the MISTLETOE study. 49 Chapter 10 157 What is already known on this topic Second generation endometrial ablation techniques are preferable to first generation techniques in the treatment of heavy menstrual bleeding. Bipolar radiofrequency, thermal balloon, and microwave ablation techniques are the most com- monly used and can safely be offered under local anaesthesia but there are insufficient data to recommend any particular technique. What this study adds Bipolar radiofrequency endometrial ablation shows significant benefit in terms of amenorrhea rates compared with thermal balloon ablation, as does microwave ablation, but there is no evi- dence of any benefit of bipolar radiofrequency over microwave ablation. There is no evidence of greater dissatisfaction with any treatment in comparisons of bipolar radi- ofrequency, thermal balloon, or microwave ablation. Other and emerging methods of second generation endometrial ablation require more rigorous evaluation. Supplementary Material Data supplements available at http://dx.doi.org/10.1136/bmj.e2564 Acknowledgments We thank all authors of identified trials who sent data through the previous related review.18 The following authors provided us with individual patient data from their trials for this review: J Abbott, University of New South Wales, Sydney, Australia; M Y Bongers, Maxima Medical Centre, Veldhoven, Netherlands; J-L Brun, Hopital Universitaire Pellegrin, Bordeaux, France; T J Clark, Birmingham Women’s Hospital, Birmingham, UK; J Cooper (2004 trial), data supplied by Micro- sulis Medical, Hampshire, UK; K G Cooper, Aberdeen Royal Infirmary, Aberdeen, UK; S L Corson (2001 trial), data supplied by Boston Scientific Corporation, Marlborough, US; J Hawe, Countess of Chester Hospital, Chester, UK; W R Meyer; data supplied by Ethicon, NJ, US; J P M Penninx, Maxima Medical Centre, Veldhoven, Netherlands; A M Sambrook, Aberdeen Royal Infirmary, Aberdeen, UK; I A van Zon-Rabelink, Medical Spectrum Twente, Enschede, Netherlands. HMB Network Meta-analysis 158

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Clinical outcomes from a randomised comparison of microwave endometrial ablation with thermal balloon endometrial ablation for the treatment of heavy menstrual bleeding. BJOG 2009;116:1038-45. 34 Bongers MY, Bourdrez P , Mol BW, Heintz AP , Brolmann HA. Randomised controlled trial of bipolar radio-frequency endometrial ablation and balloon endometrial ablation. BJOG 2004;111:1095-102. 35 Abbott J, Hawe J, Hunter D, Garry R. A double-blind randomized trial comparing the Ca- vaterm and the NovaSure endometrial ablation systems for the treatment of dysfunctional uterine bleeding. Fertil Steril 2003;80:203-8. 36 Brun JL, Burlet G, Galand B, Quereux C, Bernard P . Cavaterm thermal balloon endometri- al ablation versus hysteroscopic endometrial resection to treat menorrhagia: the French, multicenter, randomized study. J Min Invasive Gynecol 2006;13:424-30. 37 Cooper J, Anderson TL, Fortin CA, Jack SA, Plentl MB. Microwave endometrial ablation vs rollerball electroablation for menorrhagia: a multicenter randomized trial. J Am Assoc Gynecol Laparoscop 2004;11:394-403. 38 Hawe J, Abbott J, Hunter D, Phillips G, Garry R. A randomised controlled trial compar - ing the Cavaterm endometrial ablation system with the Nd:YAG laser for the treatment of dysfunctional uterine bleeding. BJOG 2003;110:350-7. 39 Van Zon-Rabelink IA, Vleugels MPH, Merkus HMWM, de Graaf R. Efficacy and satisfac- tion rate comparing endometrial ablation by rollerball electrocoagulation to uterine bal- loon thermal ablation in a randomised controlled trial. Eur J Obstet Gynecol Reprod Biol 2004;114:97-103. 40 Pellicano M, Guida M, Acunzo G, Cirillo D, Bifulco G, Nappi C. Hysteroscopic transcer - vical endometrial resection versus thermal destruction for menorrhagia: a prospective randomized trial on satisfaction rate. Am J Obstet Gynecol 2002;187:545-50. 41 Soysal ME, Soysal SK, Vicdan K. Thermal balloon ablation in myoma-induced menor - rhagia under local anesthesia. Gynecol Obstet Investigation 2001;51:128-33. 42 Corson SL, Brill AI, Brooks PG, Cooper JM, Indman PD, Liu JH, et al. One-year results of the vesta system for endometrial ablation. J Am Assoc Gynecol Laparoscop 2000;7:489- 97. 43 Romer T. Therapy of recurrent menorrhagia—Cavaterm balloon coagulation versus roller- ball endometrium coagulation—a prospective randomized comparative study. Zentralbl Gynakol 1998;120:511-4. Chapter 10 161 44 Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA 2003;289:2534-44. 45 Boujida VH, Philipsen T, Pelle J, Joergensen JC. Five-year follow-up of endometrial ablation: endometrial coagulation versus endometrial resection. Obstet Gynecol 2002;99:988-92. 46 Lethaby A, Hickey M. Endometrial destruction techniques for heavy menstrual bleeding. Cochrane Database Syst Rev 2005;4. 47 Kilonzo MM, Sambrook AM, Cook JA, Campbell MK, Cooper KG. A cost-utility analysis of microwave endometrial ablation versus thermal balloon endometrial ablation. Value Health 2010;13:528-34. 48 Yin C-S. Pregnancy after hysteroscopic endometrial ablation without endometrial preparation: a report of five cases and a literature review. Taiwan J Obstet Gynaecol 2010;49:311-9. 49 Overton C, Hargreaves J, Maresh M. A national survey of the complications of endometrial destruction for menstrual disorders: the MISTLETOE study. Minimally invasive surgical tech- niques—laser, endothermal or endoresection. BJOG 1997;104:1351-9. HMB Network Meta-analysis 162 163 Chapter 11 The measurement properties of the menorrhagia multi-attribute quality-of-life scale: a psychometric analysis 164 Chapter 11

Menorrhagia (heavy blood loss during menstruation) is a common gynaecological condition in the UK that has a significant impact on the wellbeing of many women. The number and cost of consultations and treatments impose substantial demands on the NHS. It has been estimated that 6.5% of women aged 12–51 years experience heavy menstrual bleeding (HMB), 1 with 5% of women aged 30–49 years consulting their GP each year because of the condition. 2 Women are mainly treated on the basis of symptoms, and therefore assessment of the condition and the effectiveness of treatment has a large subjective component. There is poor correlation between quasi-objective measures of menorrhagia, e.g. self-reports of blood loss and patient-based health status measures. As the aim of treatment is to improve women’s wellbeing and quality of life (QoL), it is necessary to have valid and reliable instruments to measure this. A systematic review of published research assessed the quality of QoL instruments in 19 studies of menorrhagia, using a checklist of items for clinical face validity (issues relevant to patients’ ex- pectations and concerns) and items for measurement properties (including reliability, responsive- ness, criterion or construct validity and acceptability).3 The generic Short Form 36 Health Survey Questionnaire (SF-36) was the most commonly used (63% of studies). Only two studies used a condition-specific QoL instrument for menorrhagia, and although 90% complied with more than half of the criteria for measurement properties, only 37% of studies complied with more than half the criteria for face validity. The conclusion of this review, and a review conducted by the UK’s National Institute for Clinical Excellence (NICE), was that there is a need for methodologically sound, condition-specific QoL instruments in menorrhagia with clinical face validity to assess treatment outcomes. One disease-specific instrument identified as having high face validity is the menorrhagia multi- attribute scale (MMAS) developed by Shaw et al. 4 This was developed in collaboration with women with menorrhagia using multi-attribute utility method. Although the MMAS was designed to have good face and content validity, other psychometric properties of this instrument, i.e. reliability, convergent and discriminant validity, and floor and ceiling effects, could not be evalu- ated in the original study. One study reported a small advantage for the MMAS over SF-36 in predicting the management outcome for HMB, 5 but otherwise the measurement properties of the questionnaire when used in a treatment or observational study have not been reported. The aim of this study was to assess these properties of the MMAS when used within a treatment trial. Chapter 11 165

Participants All women who took part in this study were enrolled in the ECLIPSE (Effectiveness and Cost- effectiveness of Levonorgestrel-containing Intrauterine system in Primary care against Standard trEatment for menorrhagia) trial, a randomised controlled trial designed to assess the effective- ness of a levonorgestrel-containing intrauterine system in the treatment of menorrhagia [National Institute for Health Research (NIHR) Health Technology Assessment Programme (HTA) project

02/06/02]. In order to be invited into the trial, women had to be between the ages of 25 and 50 years, presenting to GPs with menorrhagia, not intending to become pregnant in the next 5 years and agreeing to be randomised. Data from the first 431 women enrolled in the trial were analysed for this study. Procedure The ECLIPSE trial, including the study reported here, received multicentre research ethics com- mittee approval. Participants completed the MMAS and a battery of other tests as part of the baseline measures for the trial after ran- domisation, but before treatment. The other tests used were the SF-36 v2, EuroQol EQ-5D and the Sexual Activity Questionnaire. Fifty women were also invited to participate in a test–retest study of the MMAS, and complete the test again within 2 weeks of the baseline measurement. MMAS The MMAS questionnaire captures the subjective consequences of menorrhagia on six domains: practical difficul- ties; social life; psychological wellbeing; physical health; work routine; and fam- ily life. Each of the six domains has four statements that represent four levels of response. Re- spondents indicate the statement that best matches their feelings for each domain. The state- ment scores derive from a weighting of the domains and a weighting of the statements in level of severity by women in the original study. Scores range from 0 (worst possible state in all domains) to 100 (best possible state in all domains). Instruments used in the validation of the MMAS 1 - Short Form 36. The SF-36 v2 is a 36-item short-form survey that measures general health- related QoL. The SF-36 is a practical and reliable way to obtain important health outcomes data in a variety of settings, measuring eight domains of health: physical functioning; role limitations because of physical health; bodily pain; general health perceptions; vitality; social functioning; role limitations because of emotional problems; and mental health. Respondents are asked to re- call how they have felt over the previous 4 weeks. It is commonly used in studies of menorrhagia. 5 Measurement properties of MMAS 166 2 - EuroQol EQ-5D. EQ-5D is a standardised instrument for use as a measure of health out- come, and is widely used in economic evaluations of medical interventions. Applicable to a wide range of health conditions and treatments, it provides a simple descriptive profile and a single index value for health status. 3 - The Sexual Activity Questionnaire. Sexual activity is an important dimension of QoL, which may be specifically affected by menorrhagia. The Sexual Activity Questionnaire (SAQ) was developed as a self-report questionnaire for use in gynaecological clinical trials, designed to be quick to complete and acceptable to the majority of women. 6 Three dimensions of perceptions of sexual activity are measured: pleasure; discomfort; habit. Psychometric analysis The measurement properties of the MMAS were assessed using traditional psychometric proce- dures. Estimates of reliability and validity were made using intra- and inter-test correlations, with an additional comparison of means for the subscales of the questionnaire. Inspection of the data supported the use of Pearson’s product-moment correlation coefficient (r) for bivariate correla- tions and analysis of variance (anova) for comparison of means. Floor and ceiling effects were also assessed using frequency data on high and low scores.

The mean age of the participants was 41.25 years (SD 5.3 years). The ethnic mix of the sample was representative of the patient population for the area, with 93% of women categorising them- selves as from the two main ethnic groups: white British (83%) and South Asian (10%). Reliability Forty-nine of the 50 women asked to take the questionnaire again within 2 weeks returned completed questionnaires. The test–retest correlation for the total MMAS score was acceptable (r = 0.836), suggesting that it is stable over time. Cronbach’s alpha was calculated as a measure of the internal consistency of the six items of the MMAS. This was 0.82, which, being within the range 0.7 and 0.9, suggests that the items are all measuring aspects of the same construct. Evi- dence of the homogeneity of the MMAS was also provided by the item–total correlations (the correlation between each item and the total score minus that item), which range between 0.44 and 0.68. Only one such correlation fell below 0.6: that for ‘practical difficulties’ caused by menorrhagia. Chapter 11 167 Validity The MMAS has already been shown to have good face validity, so this analysis concentrated on construct validity: i.e. the extent to which the instrument measures what it is intended to meas- ure. An important method of demonstrating construct validity is by showing that an instrument correlates with other instruments measuring similar constructs, e.g. generic QoL scales (con- vergent validity), and does not correlate with measures of different constructs, e.g. age or body mass index (discriminant validity). Convergent validity To show convergent validity, correlations between test scores should be moderate to high: i.e. equal to or above 0.4. Table 1 shows the correlations between the MMAS total score, the sub- scales of the SF-36 and the EQ-5D (note that whereas all participants completed all items of the MMAS at baseline, some missed items in the SF-36). These show mod- erate correlations for most components of the SF-36, but weaker correlations for physical functioning, general health perception and for the EQ-5D standardised score. Table 1 Correlations between the MMAS total score and the EQ-5D summary and SF-36 subscales. The individual domain scores of the MMAS were compared with the SF-36 subscales. With the exception of the practical difficulties domain on the MMAS, which did not significantly correlate with any SF-36 subscale, the highest correlations were between each of the MMAS domains and consistency of the six items of the MMAS. This was 0.82, which, being within the range 0.7 and 0.9, suggests that the items are all measuring aspects of the same construct. Evi- dence of the homogeneity of the MMAS was also provided by the item–total correlations (the correlation between each item and the total score minus that item), which range between 0.44 and 0.68. Only one such correlation fell below 0.6: that for ‘practical difficulties’ caused by menorrhagia. Validity The MMAS has already been shown to have good face validity, so this analysis concentrated on construct validity: i.e. the extent to which the instrument measures what it is intended to measure. An important method of demonstrat- ing construct validity is by showing that an instrument cor- relates with other instruments measuring similar constructs, e.g. generic QoL scales (convergent validity), and does not correlate with measures of different con- structs, e.g. age or body mass index (discriminant validity). Convergent validity To show convergent validity, correlations between test scores should be moderate to high: i.e. equal to or above 0.4. Table 1 shows the correlations between the MMAS total score, the subscales of the SF-36 and the EQ-5D (note that whereas all participants completed all items of the MMAS at baseline, some missed items in the SF-36). These show mod- erate correlations for most components of the SF-36, but weaker correlations for physical functioning, general health perception and for the EQ-5D standardised score. The individual domain scores of the MMAS were com- pared with the SF-36 subscales. With the exception of the practical difficulties domain on the MMAS, which did not significantly correlate with any SF-36 subscale, the highest correlations were between each of the MMAS domains and the SF-36 social functioning scale. The correlation between the psychological health scales of the two instruments is 0.39, and that between the MMAS relationships scale and the SF-36 emotional role limitations is 0.47. However, these correlations of subscales should be interpreted with caution as there are only four points on the MMAS subscales. So, to investigate these relationships further, respondents were divided into four groups for each MMAS domain, and their scores on the SF-36 were compared using anova. The

for most subscales and domains were highly signifi- cant for each comparison, with high scores on the MMAS corresponding to high scores on the SF-36. The exception again was for comparisons in the practical difficulties domain. Here, three comparisons were not significant: men- tal health ( F 3,422 = 1.66; p = 0.175); pain ( F3,424 = 0.62; p = 0.60); and general health ( F3,415 = 2.21; p = 0.09). There was a small, non-significant difference in the total MMAS scores of women reporting that they were not engaging in sexual activity on the SAQ and those who were (38.86 and 41.49, respectively). It may be that the MMAS relationship domain reflects a particular problem with sex- ual relationships. To test this, comparisons were made between the scores on the pleasure, discomfort and habit scales of the SAQ for women scoring at the four different levels of the relationship domain. This revealed a significant effect of level on the discomfort scale ( F 3,321 = 4.05; p = 0.008), but insignificant effects of pleasure (F3,321 = 1.71; p = 0.165) and habit ( F3,326 = 2.54; p = 0.057). Discriminant validity The MMAS is a condition-specific measure, and so should not be affected by variables that are not directly related to variation within the condition. So the total MMAS score would not be expected to correlate with age or body mass index (BMI). As expected, these correlations are very low: age r = 0.086; BMI r = )0.057. As well as providing evi- dence for the validity of the MMAS, it suggests that it can be used with all age groups. Acceptability All items in the MMAS were completed by all participants, in contrast to the other instruments, e.g. SF-36, where par- ticipants missed various sections of the questionnaire. We would suggest that this indicates that the MMAS was acceptable to participants, and that the questions were seen as relevant to their condition. Floor and ceiling effects In psychometric instruments these have implications for the precision of the instrument and its responsiveness to change, as they reduce the likelihood that the instrument will measure further improvement or deterioration. In this Table 1. Correlations between the MMAS total score and the EQ-5D summary and SF-36 subscales MMAS total rn SF-36 subscales Physical functioning 0.33 420 Physical role limitations 0.45 422 Emotional role limitations 0.49 421 Social functioning 0.54 427 Mental health 0.40 426 Energy/vitality 0.42 426 Pain 0.38 428 General health 0.32 419 EQ-5D summary score 0.32 428 Pattison et al. 1530 ª 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2011 RCOG Measurement properties of MMAS 168 the SF-36 social functioning scale. The correlation between the psychological health scales of the two instruments is 0.39, and that between the MMAS relationships scale and the SF-36 emotional role limitations is 0.47. However, these correlations of subscales should be interpreted with caution as there are only four points on the MMAS subscales. So, to investigate these rela- tionships further, respondents were divided into four groups for each MMAS domain, and their scores on the SF-36 were compared using anova. The results for most subscales and domains were highly significant for each comparison, with high scores on the MMAS corresponding to high scores on the SF-36. The exception again was for comparisons in the practical difficulties domain. Here, three comparisons were not significant: mental health (F 3,422 = 1.66; p = 0.175); pain (F3,424 = 0.62; p = 0.60); and general health (F3,415 = 2.21; p = 0.09). There was a small, non-significant difference in the total MMAS scores of women reporting that they were not engaging in sexual activity on the SAQ and those who were (38.86 and 41.49, re- spectively). It may be that the MMAS relationship domain reflects a particular problem with sexual relationships. To test this, comparisons were made between the scores on the pleasure, discom- fort and habit scales of the SAQ for women scoring at the four different levels of the relationship domain. This revealed a significant effect of level on the discomfort scale (F 3,321 = 4.05; p = 0.008), but insignificant effects of pleasure (F3,321 = 1.71; p = 0.165) and habit (F3,326 = 2.54; p =0.057). Discriminant validity The MMAS is a condition-specific measure, and so should not be affected by variables that are not directly related to variation within the condition. So the total MMAS score would not be ex- pected to correlate with age or body mass index (BMI). As expected, these correlations are very low: age r = 0.086; BMI r = 0.057. As well as providing evidence for the validity of the MMAS, it suggests that it can be used with all age groups. Acceptability All items in the MMAS were completed by all participants, in contrast to the other instruments, e.g. SF-36, where participants missed various sections of the questionnaire. We would suggest that this indicates that the MMAS was acceptable to participants, and that the questions were seen as relevant to their condition. Floor and ceiling effects In psychometric instruments these have implications for the precision of the instrument and its responsiveness to change, as they reduce the likelihood that the instrument will measure further improvement or deterioration. In this sample five (1.2%) women’s scores were the lowest pos- sible and three (0.7%) were the highest possible. The overall distribution of scores was slightly positively skewed (skew = 0.41; SE = 0.12), which is what might be expected in a sample of Chapter 11 169 women just about to embark on treatment for menorrhagia. These statistics indicate that there are no floor or ceiling effects.

This study investigated further the psychometric properties of the MMAS, a menorrhagia-specific QoL instrument. It has shown that in addition to having high face validity, the MMAS has good convergent and discriminant validity and test–retest reliability. It also has high internal consis- tency, with a Cronbach’s alpha score of 0.82, which is further evidence of reliability and indicates that all the items are measuring different aspects of the same construct. The overall MMAS showed moderate correlations with most of the subscales of the SF-36. Low- er correlations were found for physical functioning and general health perception. Rather than being a negative feature these low correlations may reflect the inappropriateness of the SF-36 for measuring QoL in women with heavy menstrual bleeding. The physical functioning subscale is heavily weighted towards mobility and self-care, which are not likely to be affected by HMB. The general health subscale and the EQ-5D, which were also relatively poorly correlated with the MMAS, may not be precise enough to measure differences in this patient group, especially when women are asked to consider their general condition rather than that pertaining to their menstrual cycle. Conversely, scores on the practical difficulties subscale of the MMAS were not related to other QoL measures. This domain of the MMAS is very specific to menorrhagia, relating to sanitary protection, flooding, etc., and may pick up specific important issues not measured by more general scales. All women completed the whole of MMAS, which suggests that it is acceptable to women and seen to be relevant. It could be argued that this sample was more highly motivated than women with HMB more generally, because they had already agreed to take part in the ECLIPSE trial. However, there were missing data in other questionnaires administered at the same time. We have not at this stage been able to assess the sensitivity of the MMAS to changes in treat- ment. However, the findings of the ECLIPSE trial will enable us to report on this in due course.

These results suggest that the MMAS has good measurement properties, and is therefore an appropriate condition-specific instrument to measure the outcome of treatment for HMB. Measurement properties of MMAS 170

Firstly we would thank all the women who agreed to participate in this study. We thank all staff in primary and secondary care involved in the recruitment of participants to the ECLIPSE study and delivery of baseline questionnaires. We also thank Laura Gerrard, the trial co-ordinator, Lisa Leighton, the trial administrator, and Lee Middleton of the Birmingham Clinical Trials Unit for pre- paring the data for analysis. Chapter 11 171

1 Harlow SD, Campbell OMR. Epidemiology of menstrual disorders in developing coun- tries: a systematic review. BJOG 2004;111:6–16. 2 Vessey MP , Villardmackintosh L, McPherson K, Coulter A, Yeates D. The Epidemiology of Hysterectomy—Findings in a large cohort study. BOJG 1992;99:402–7. 3 Clark TJ, Khan KS, Foon R, Pattison H, Bryan S, Gupta JK. Quality of life instruments in studies of menorrhagia: a systematic review. Eur J Obstet Gynecol Reprod Biol 2002;104:96–104. 4 Shaw RW, Brickley MR, Evans L, Edwards MJ. Perceptions of women on the im- pact of menorrhagia on their health using multi-attribute utility assessment. BOJG 1998;105:1155–9. 5 Habiba M, Julian S, Taub N, Clark M, Rashid A, Baker R, et al. Limited role of multi- attribute utility scale and SF-36 in predicting management outcome of heavy menstrual bleeding. Eur J Obstet Gynecol Reprod Biol 2010;148:81–5. 6 Stead ML, Crocombe WD, Fallowfield LJ, Selby P , Perren TJ, Garry R, et al. Sexual activ- ity questionnaires in clinical trials: acceptability to patients with gynaecological disorders. BJOG 1999;106:50–4. Measurement properties of MMAS 172 173 Chapter 12 Summary and Discussion 174 Chapter 12 - Summary and Discussion

The first part of this thesis presents the results of the LUNA trial to determine the efficacy of laparoscopic uterosacral nerve ablation (LUNA) for chronic pelvic pain (CPP), a multicentre trial coordinated by the University of Birmingham Clinical Trials Unit, and the subsequent individual patient data (IPD) meta-analysis of this and all other comparable trials. A review of psychological therapies is also presented. The second part of the thesis was undertaken as part of a commis- sioned project from the National Institute for Health Research Health Technology Assessment programme and assessed, by systematic review, the effectiveness of the levonorgestrel releasing intra-uterine system (LNG-IUS, Mirena®), hysterectomy and endometrial ablation in the treatment of heavy menstrual bleeding (HMB). The measurement properties of a quality of life instrument for heavy menstrual bleeding were also assessed. The introduction (Chapter 1) defines the two benign gynaecological conditions, chronic pelvic pain and heavy menstrual bleeding, highlighting the burden to women and health care systems and describes the symptoms, aetiology and epidemiology for both. Chapter 2 provides a complete clinical overview of chronic pelvic pain. The importance of tak- ing a careful and thorough history to prompt further investigations is emphasised, particularly in view that an organic cause is not found at laparoscopy in at least a third of women with chronic pelvic pain. The biopsychosocial model of pain is discussed and consideration of psychological symptoms highlighted. The absence of effective gynaecological treatments is discussed and a multidisciplinary approach is recommended. Chapter 3 sets the scene for the randomised trial by describing the state of clinical practice in the UK gynaecological community. We undertook a national survey and found around 45% of respondents performed LUNA, of whom three quarters used the procedure for chronic pelvic pain and just under two-thirds employed it for endometriosis. However, 81% of surgeons were prepared to randomise patients into a clinical trial of LUNA versus no intervention, demonstrating that equipoise existed amongst gynaecologists and a clinical trial was warranted. The protocol for the LUNA trial is detailed in Chapter 4. Women with chronic pain of greater than 6 months duration, in whom diagnostic laparoscopy revealed either no pathology or mild endometriosis, were eligible. Consenting, eligible women were randomised during laparoscopy to undergo immediate uterosacral nerve ablation or no LUNA. Women were blinded to the allo- Chapter 12 175 cation by use of a sham incision in the no LUNA group. Pelvic pain was measured using a visual analogue scale, with general quality of life and sexual activity as secondary outcomes. Women responded by postal questionnaire at 3, 6 and 12 months after randomisation. Pre-specified sub-groups included the presence or absence of some minimal pathology, the site of pain and parity. Analysis was by intention to treat. The sample size required to detect a difference of two points on a ten centimetre scale, allowing for 20% loss to follow-up, was 440 participants. Chapter 5 reports the results of the LUNA trial. After a median follow up of 69 months, there were no significant differences between the visual analogue pain scales for the worst pain reported (mean difference (MD) between LUNA group and No LUNA group -0·04cm, 95% confidence interval (CI), -0·33 to 0·25cm; p=0·80), non-cyclical pain (-0·11cm, 95%CI -0·50 to 0·29cm; p=0·60) dysmenorrhoea (-0·09cm, 95%CI -0·49 to 0·30cm; p=0·60), or dyspareunia (0·18cm, -0·22 to 0·62cm; p=0·40). No differences were observed between the LUNA group and the No LUNA group for quality of life. We concluded LUNA did not result in improvements in pain, dys- menorrhea, dyspareunia or quality of life, compared to laparoscopy without pelvic denervation. Chapter 6 describes the protocol for a meta-analysis collecting IPD from the existing trials, to provide a comprehensive assessment of the effectiveness of LUNA. We updated searches, con- tacted the authors of identified trials to obtain IPD and explored any heterogeneity. Pain scores were calibrated to a 10 point scale and were analysed using a multilevel model allowing for repeated measures. Chapter 7 reports the results of the IPD meta-analysis. Raw data were available from 862 women randomised into five trials. There was no significant difference between LUNA and No LUNA for the worst pain recorded over a 12 month time period (MD: 0.25 points in favour of No LUNA on a 0-10 point scale, 95% CI: -0.08 to 0.58; p=0.1). This IPD meta-analysis reinforces the conclu- sions drawn from our LUNA trial that the procedure is not effective in alleviating pain within one year of treatment. The effectiveness of psychological therapies for CPP was evaluated in a systematic review, de- scribed in Chapter 8. The selected four studies involving women with CPP were randomized controlled trials of psychological therapies compared to no treatment or standard gynecological treatment. Compared to no psychological intervention, therapy produced a standardized mean difference (SMD) of -3.27 (95% CI -4.52 to -2.02) and 1.11 (95% CI -0.05 to 2.27) at 3 months and -3.95 (95%CI -5.35 to -2.55) and 0.54 (95%CI -0.78 to 1.86) at 6 months and greater, based on a visual analog scale score of 0-10. The current evidence does not allow us to conclude whether psychological interventions have an effect on self-reported pain scores in women with CPP . Summary and Discussion 176 In Chapter 9, we undertook an IPD meta-analysis to evaluate the relative effectiveness of hyster- ectomy, endometrial destruction (both ‘first generation’ hysteroscopic and ‘second generation’ non-hysteroscopic techniques) and LNG-IUS for HMB. Data on 2814 women were available from 17 of the 30 randomised controlled trials identified. At around 12 months, 7.3% (12.6% v 5.3%) more women were dissatisfied with outcome of first generation hysteroscopic techniques than hysterectomy (Odds Ratio (OR): 2.46, 95%CI:1.54-3.93, p=0.0002), but hospital stay (Weighted Mean Difference (WMD): 3.0 days, 95%CI:2.9-3.1, p<0.00001) and time to resumption of normal activities (WMD: 5.2 days, 95%CI:4.7-5.7, p<0.00001) were longer for hysterectomy. Unsat- isfactory outcomes were comparable with first and second generation techniques (OR: 1.20, 95%CI:0.88-1.62, p=0.2), although second generation techniques were quicker (WMD:14.5 minutes, 95%CI:13.7-15.3, p<0.00001) and women recovered sooner (WMD: 0.48 days, 95%CI:0.20-0.75, p=0.0008) with fewer procedural complications. More women are dissatis- fied following endometrial destruction than hysterectomy. However, dissatisfaction rates are low after all treatments and hysterectomy is associated with increased hospital stay and recovery period. Definitive evidence on effectiveness of LNG-IUS compared to more invasive procedures is lacking. In chapter 10, we extended the previous review to determine the relative effectiveness of second generation ablation techniques in the treatment of heavy menstrual bleeding. Nineteen ran- domised controlled trials (involving 3287 women) were identified. Of the three most commonly used techniques, network meta-analysis showed that bipolar radiofrequency and microwave ablation resulted in higher rates of amenorrhoea than thermal balloon ablation at around 12 months (OR: 2.51, 95%CI 1.53 to 4.12, p<0.001; and 1.66, 1.01 to 2.71, p=0.05, respectively), but there was no evidence of a convincing difference between the three techniques in the num- ber of women dissatisfied with treatment or still experiencing heavy bleeding. Compared with bipolar radio frequency and microwave devices, an increased number of women still experienced heavy bleeding after free fluid ablation (OR: 2.19, 95%CI 1.07 to 4.50, p=0.03; and 2.91, 1.23 to 6.88, p=0.02, respectively). Compared with radio frequency ablation, free fluid ablation was associated with reduced rates of amenorrhoea (OR: 0.36, 95%CI 0.19 to 0.67, p=0.004) and increased rates of dissatisfaction (OR: 4.79, 95%CI 1.07 to 21.5, p=0.04). We concluded bipolar radio frequency and microwave ablative devices are more effective than thermal balloon and free fluid ablation in the treatment of heavy menstrual bleeding with second generation endometrial ablation devices. Finally, in Chapter 11, the reliability and validity of the Menorrhagia Multi-Attribute Scale (MMAS), a menorrhagia-specific quality of life instrument, was investigated. The MMAS was found to have good measurement properties and is therefore an appropriate condition-specific instrument to measure the outcome of treatment for HMB. Chapter 12 177 Chronic Pelvic Pain CPP represents a significant disease burden in both primary and secondary care 1. A diagnosis of idiopathic CPP is arrived at once all other organic causes of pain are excluded by diagnostic laparoscopy. That is not to say that idiopathic CPP is a psychogenic condition. Endometriosis, pelvic adhesions, chronic pelvic inflammatory disease, and ovarian cysts were the pathologies most frequently observed at laparoscopy in women with CPP in the LUNA Trial. 2 Moreover, the severity of pain is not related to severity of underlying pathology, as illustrated by endometriosis, where stage of disease is poorly correlated with reported pain. 3 CPP is seldom caused by a sin- gle factor alone and psychological symptoms may be both causative and associative. A troublesome clinical issue is the lack of an accurate tool to efficiently diagnose and direct cases of patients.4 The Royal College of Obstetricians and Gynaecologists (RCOG) guidelines provide a number of suggested initial investigations, including history, microbiological screening and vagi- nal examination, all with weak evidence for utility. 5 If no cause of the pain is found, the first port of call would usully be to perform a diagnostic laparoscopy, although the RCOG guidelines now suggest it may be better seen as a second line investigation if other therapeutic options have failed. 5 The parasympathetic ganglia and nerve plexuses in the uterosacral ligaments are believed to carry the somatic pain from the pelvis to the pain, thus theoretically, ablation of these nerve trunks should offer pain relief. Neuroablation at the time of diagnostic laparoscopy was widely practiced in the UK, 6 but its efficacy was never reliably demonstrated prior to our work. Our IPD meta- analysis reinforced the conclusions drawn from the LUNA trial that the procedure is not effective in alleviating pain within one year of treatment. Subgroup analysis did suggest a benefit of LUNA in those without visible pathology, consistent with the Cochrane review, although this effect was only seen at 12 months and was of borderline statistical significance.7 Conversely, the IPD meta- analysis of those with visible pathology showed greater decrease in pain in the No LUNA group, contradicting the Cochrane review. These subgroup effects lack biological plausibility and are likely to have arisen by chance. The failure to demonstrate an improvement in pain relief or quality of life in women who had the LUNA procedure illustrates the importance of rigorous assessment in the pursuit of evidence based medicine. Negative results are equally important as data supporting a procedure. LUNA is not without risks and costs and the findings of our research here should discourage the use of an ineffective procedure. Conversely, there is still a lack of evidence regarding the effectiveness of adhesionolysis in reduction of CPP . 8 There is insufficient evidence to comment on pain relief after hysterectomy, and reflecting similar guidelines for heavy menstrual bleeding, such a major operation perhaps should not be considered as a first line solution to pelvic pain. Summary and Discussion 178 We postulate that the initial general improvement seen over the first 6 months is attributable to the reassurance derived from being told that no serious cause had been found for their pain. A study identified in our review of psychological therapies found no difference in pain between women debriefed after laparoscopy with a photograph of their pelvis, compared with those that did not receive a photograph. 9 Grace, in her reflections from interviews with women with CPP , observes that women expect the source of pain should be “visible”, in the form of pathology, and in the absence of a laparoscopic diagnosis, tend to normalise the pain. Yet women continue to refer in their thoughts about the cause of pain to biological mechanisms, for example hormonal imbalance or pelvic trauma due to childbirth.10 Living with chronic pelvic pain requires women to develop coping strategies to maintain their daily family and working lives. Cognitive behavioural therapy (CBT) may help with this. CBT involves encourages women to first assess the thoughts associated with pain, and the extent and consequences of such thinking. The goal then is to develop adaptive coping behaviour that seeks to achieve positive goals. CBT has demonstrated to be effective in improving mood and may be useful in reducing pain and disability in a review of many musculoskeletal chronic pain, 11 but the effectiveness for CPP is unproven. Future research in the management of CPP CPP can be viewed in a ‘biopsychosocial’ model, in which underlying ‘disease’ states interact with psychological and social factors to produce the symptoms experienced. 12 This approach demands a multidisciplinary approach to management and there is some evidence that this

in improved quality of life, if not reduced pain, 13 but further health service research is re- quired. Such multidisciplinary care should be considered as a complex intervention, built up from a number of components, each of which may act both independently and inter-dependently. The components usually include treatment activities e.g. psychological therapy, parameters of these activities e.g. frequency, timing in relation to other aspects of management and methods of organising those activities e.g. group sessions or CBT by telephone. Sometimes is difficult to identify the most efficacious components within a multidisciplinary care approach and it is not necessarily enough to conduct randomised trials of individual components and assume that put- ting together those activities that are of benefit will produce a synergistic effect. Optimisation of a multidisciplinary approach will require a coordinated programme of research, modelled upon the Medical Research Council’s Framework for the development and evaluation of complex in- terventions. 14 Future trials should also consider the recommendations of the IMMPACT initiative and employ outcome measures that not only capture the intensity of pain, but the effect on physical and emo- tional functioning.15 If pharmacological treatments are to be assessed, the use of titrated dosing and a minimum treatment period of 3 months are recommended in order to identify respond- ers.16 New trials should have larger numbers,17,18 aiming to recruit 350 or more patients to detect Chapter 12 179 a more realistic, but worthwhile, effect of any intervention. To explore when the benefit emerges and whether it is maintained, longer follow-up of participants is recommended. In chronic condi- tions where outcomes may vary over time, repeated measures analyses will maximize statistical power from the trial sample. Finally, to truly capture the impact of CPP on a woman’s life, a dis- ease specific instrument, developed and validated by rigorous methods, and driven by accounts of symptoms and burden from women with CPP , needs to be develop in order to assess the effectiveness of future treatments. Heavy Menstrual Bleeding Heavy menstrual bleeding (HMB) is a common problem that can significantly impact on women’s lives, and burden individuals and healthcare systems.19,20 A range of non-hormonal and hormonal medical treatments are available as first line therapy for women presenting with HMB in primary care. ECLIPSE, a recent large, pragmatic randomized trial found both LNG-IUS and usual medi- cal treatments reduce the adverse impact of HMB on women’s lives over two years, but LNG-IUS is the more effective.21 Discontinuation rates for LNG-IUS in our review were 28% by two years, comparable to ECLIPSE where 31% of those who had the system fitted had it removed, pre- dominantly for perceived lack of effectiveness or irregular or prolonged bleeding. When medical treatments fail to provide adequate relief, surgical interventions, including hys- terectomy or endometrium destruction, can be considered. 22 A rapid decrease in the number of hysterectomies has been observed in the UK, 23 with a corresponding rise in the number of endometrial ablations, 24 but overall, surgical procedures are decreasing, which can perhaps be ascribed to the increasing use of LNG-IUS over the last decade. This is reflected in the ECLIPSE trial, where 6% (32 of 571 women randomised) had hysterectomies within 2 years, yet 5% (28/571) had endometrial ablation. Our review found that both first and second generation endometrial destruction techniques are associated with higher dissatisfaction rates than hyster- ectomy, although all three procedures provided high levels of satisfaction, with small absolute differences. The predicted dominance of endometrial destruction is neither being witnessed nor may be warranted. 24 The results of an current randomised trial of LNG-IUS compared with a second generation endometrial device also help resolve the question as to first line treatment.25 Technological developments may influence the further uptake of endometrial destruction. Whilst our review found no statistically significant difference in amenorrhea rates between first and second generation techniques, the latter were clearly quicker to perform, and enabled women to return to work and normal activities more quickly. 26 Comparing second generation techniques, bipolar radiofrequency ablation seems to offer benefits over thermal balloon in terms of amenor- rhea rates and is procedurally quicker than thermal balloon and microwave ablation.27 Again, this Summary and Discussion 180 is reflected in UK usage data, with radiofrequency ablation techniques being the most rapidly ris- ing procedure. Whether this market share is sustained will depend on the emergence of simpler, next generation devices, the replacement chosen by users of the microwave ablation system and the increasing pace of out-patient based procedures. Pain, from cervical dilation and vasovagal reactions are limiting factors for the wider use of out- patient procedures. Only two studies have evaluated the use of any endometrial device under lo- cal anaesthesia,28,29 both of which employed intracervical anaesthesia. The efficacy of intra- and paracervical anaesthesia in reducing pain during diagnostic hysteroscopy has been demonstrat- ed, 30 but data on the most effective anaesthetic for interventional procedures is lacking. Other aspects, such as the distension media, diameter of the ablative device, and the use of speculum and other cervical instruments may also influence patient discomfort with the procedure. Ulti- mately, the decision should be left to the women’s preference and the operator’s experience. There has been a long term interest in progesterone antagonists and selective progesterone re- ceptor modulators for treatment for idiopathic HMB and HMB associated with uterine fibroids. 31 Recently, a pair of randomised trials has recently demonstrated the effectiveness of the ulipristal acetate in reducing fibroid size and quickly inducing amenorrhea. 32,33 However, reversible chang- es to the endometrium have been witnessed,34 limiting their indication to short-term pre-operative use. There is potential for use of ulipristal as a first line, long term treatment for heavy menstrual bleeding associated with uterine fibroids, but not without further data on the long-term safety in this population. Future Research in Heavy Menstrual Bleeding Any further developments in endometrial ablation devices should be compared against the bipo- lar radiofrequency procedure before widespread adoption. New thermal balloon devices are now on the market which are suitable for the out-patient setting and have shorter treatment cycles. Evidence-based improvements in pain management for diagnostic hysteroscopy should be ex- plored in interventional procedures. The UK guidelines for heavy menstrual bleeding recommend that for women with a normal uter- us, endometrial ablation should be considered preferable to hysterectomy, 35 whilst our review in- dicates higher levels of dissatisfaction with endometrial ablation.26 It has been suggested that this difference might be amplified if laparoscopic sub-total hysterectomy was performed, in contrast to the total hysterectomies predominant in the contributing studies. However, a Cochrane review failed to corroborate anecdotal evidence of improved sexual, bowel or urinary outcomes after sub-total hysterectomy.36 A randomized trial of sub-total hysterectomy compared with second generation ablative techniques would address this uncertainty. Chapter 12 181 The current epidemiological data on the prevalence of heavy menstrual bleeding are derived from regional surveys and are out-of-date.37,38 It is also likely that those presenting in primary care represent only a minority of women experiencing difficulties with their periods. A shift in empha- sis away from menstrual blood loss to a more patient-centred definition of HMB that interferes with women’s physical, emotional and social life, is advocated.39 Thus, the priority for healthcare providers should be to respond to the impact of HMB on women’s day-to-day lives, 40 basing treatment decisions on evidence using patient reported outcomes, such as the validated Multi- attribute Menorrhagia Assessment Scale.35,41,42 Summary and Discussion 182 Nederlandse samenvatting In het eerste deel van dit proefschrift wordt de LUNA studie over de effectiviteit van laparoscopis- che uterosacrale zenuw ablatie (LUNA) voor chronische pelviene pijn besproken. De LUNA studie is een multicenter onderzoek gecoördineerd door de universiteit van Birmingham Clinical Trials Unit. Daarnaast bevat het eerste deel de daaropvolgende meta-analyse met individuele patiënt- gegevens (IPD) van deze en alle andere vergelijkbare studies. Ook wordt een overzicht van psy- chologische therapieën wordt ook gepresenteerd. Het tweede deel van het proefschrift werd verricht in het kader van een project in het kader van het programma van het nationale instituut voor Health Research Health Technology Assessment. Binnen dit project werd via een systematische review verricht naar de effectiviteit van de lev- onorgestrel houdend intra-uteriene spiraal (LNG-IUS), hysterectomie en endometrium ablatie in de behandeling van hevige menstruele bloedingen (HMB). Ook werden de meet eigenschappen van een kwaliteit van leven instrument voor hevige menstruele bloedingen beoordeeld. De inleiding (hoofdstuk 1) definieert de twee goedaardige gynaecologische aandoeningen, chro- nische bekken pijn in het en menorrhagie (hevige menstruatie), de symptomen, etiologie en epi- demiologie en beschrijft de impact op vrouwen en op het zorgsysteem. Hoofdstuk 2 geeft een compleet klinisch overzicht van het ziektebeeld chronische pelviene pijn. Het belang van het afnemen van een zorgvuldige en grondige anamnese wordt benadrukt, met name gezien het feit dat dat een organische oorzaak in ten minste een derde van de vrouwen met chronische pelviene pijn niet wordt gevonden bij laparoscopie. Het biopsychosociale model van pijn wordt besproken en betekenis van psychische klachten wordt gemarkeerd. Vervolgens wordt het ontbreken van effectieve gynaecologische behandelingen besproken en wordt een multidisciplinaire aanpak wordt aanbevolen. Hoofdstuk 3 beschrijft de noodzaak voor een gerandomiseerde studie aan de hand van een be- schrijving van de klinische praktijk in het Verenigd Koninkrijk. We vonden in een nationaal onder- zoek dat ongeveer 45% van de respondenten LUNA gebruikt, van wie driekwart de procedure voor chronische pelviene pijn gebruikte en tweederde voor endometriose. Het bleek dat 81% van de gynaecologen bereid was om patiënten the randomiseren in de LUNA trial. Gezien deze ‘equipoise’ bleek een klinisch onderzoek gerechtvaardigd was. Het protocol voor de LUNA trial is beschreven in hoofdstuk 4. Vrouwen met langer dan 6 maanden bestaande pelviene pijn, die bij diagnostische laparoscopie geen pathologie of milde endome- Chapter 12 183 triose hadden, kwamen in aanmerking. Na geïnformeerde toestemming, werden in aanmerking komende vrouwen tijdens laparoscopie gerandomiseerd voor directe uterosacrale zenuw ablatie of geen interventie. Vrouwen bleven geblindeerd voor de toewijzing door het gebruik van een schijnincisie in de controle groep. Vervolgens werd pelviene pijn gemeten met behulp van een visuele analoge schaal, met een algemene kwaliteit van leven vragenlijst en seksuele activiteit als secundaire uitkomsten. Deelne- mers vulden vragenlijsten in op 3, 6 en 12 maanden na randomisatie. Vooraf gespecificeerde subgroepen omvatten de aanwezigheid of afwezigheid van een minimale pathologie, de plaats van de pijn en pariteit. Analyse gebeurde volgens intention to treat. De steekproefgrootte nodig om een verschil van twee punten te kunnen detecteren op een tien centimeter schaal, gecor - rigeerd voor 20% verlies voor follow-up, was 440. Hoofdstuk 5 beschrijft de resultaten van de LUNA trial. Na een mediane follow-up van 69 maanden waren er geen significante verschillen tussen de visuele analoge pijnschalen voor de gerapporteerde ergste pijn (gemiddeld verschil (MD) tussen LUNA groep en geen LUNA groep -0.04cm, 95% betrouwbaarheidsinterval (BI) , -0.33 tot 0.25cm, p = 0.80), niet-cyclische pijn (-0.11cm, 95% CI -0.50 tot 0.29cm, p = 0.60), dysmenorroe (-0.09cm, 95% CI -0.49 tot 0.30cm, p = 0.60), of dyspareunie (0.18cm, -0.22 tot 0.62cm, p = 0.40). Er werden geen verschillen waargenomen tussen de LUNA groep en de controle-groep voor kwaliteit van het leven. Wij concludeerden dat LUNA niet resulteert in verbetering van de pijn, dysmenorroe, dyspareunie en kwaliteit van leven, vergeleken met laparoscopie zonder LUNA. Hoofdstuk 6 beschrijft het protocol voor een meta-analyse op basis van individuele patiënten data van de bestaande studies naar de effectiviteit van LUNA. We hernieuwden zoekopdrachten, zochten contact met de auteurs van geïdentificeerde studies voor het verkrijgen van individuele patiënten data en onderzochten welke heterogeniteit. Pijnscores werden gekalibreerd op een 10-puntsschaal en werden geanalyseerd met behulp van een multilevel-model waardoor her - haalde metingen. Hoofdstuk 7 rapporteert de resultaten van de IPD meta-analyse. Ruwe data waren beschikbaar van 862 vrouwen gerandomiseerd in vijf studies. Er was geen significant verschil tussen LUNA en geen LUNA voor de ergste pijn tijdens een 12 maanden durende periode (MD: 0.25 punten in het voordeel van geen LUNA op een 0-10 schaal van, 95% BI: -0.08 tot 0.58, p = 0.1). Uit deze IPD meta-analyse blijkt dat LUNA niet effectief is in het reduceren van pelviene pijn. De effectiviteit van psychologische therapieën voor chronische pelviene pijn werd geëvalueerd in een systematische review beschreven in hoofdstuk 8. De vier geselecteerde studies over vrouwen met chronische pelviene pijn waren gerandomiseerde gecontroleerde studies waarin Summary and Discussion 184 psychologische therapieën werden vergeleken met geen behandeling of standaard gynaecolo- gische zorg. In vergelijking met geen psychologische interventie, resulteerde de therapie na 3 maanden in een gestandaardiseerd gemiddeld verschil (SMD) van -3,27 (95% CI -4.52 tot -2.02) en 1.11 (95% CI -0.05 tot 2.27) en na 6 maanden of meer in -3.95 (95% CI – 5.35 tot -2.55) en 0.54 (95% CI -0.78 tot 1.86), gebaseerd op een visuele analoge schaal score van 0-10. De huidige gegevens maken een conclusie over de effectiviteit van psychologische interventies op zelf-gerapporteerde pijnscores bij vrouwen met chronische pelviene pijn niet mogelijk. In hoofdstuk 9 ondernamen we een IPD meta-analyse naar de relatieve effectiviteit van hyster - ectomie, endometrium ablatie (zowel ‘eerste generatie’ hysteroscopische en ‘tweede generatie’ niet-hysteroscopische technieken) en LNG-IUS in de behandeling van heftig menstrueel bloed- verlies. Wij verkregen gegevens van 2814 vrouwen afkomstig van 17 van de 30 gerandomis- eerde gecontroleerde studies. Na 12 maanden, bleek 7.3% (12.6% v 5.3%) meer vrouwen waren ontevreden met het resultaat van de eerste generatie hysteroscopische ablatie dan hysterecto- mie (Odds Ratio (OR): 2.46, 95% CI :1.54 tot 3.93, p = 0.0002), maar verblijf in het ziekenhuis (Gewogen gemiddeld verschil (GGV): 3.0 dagen, 95% CI :2.9 tot 3.1, p <0.00001) en de tijd tot hervatting van de normale activiteiten (GGV: 5.2 dagen, 95% CI :4.7 tot 5.7, p <0.00001) waren langer voor hysterectomie. Ontevredenheid met het behandelresultaat trad in vergelijkbare mate op tussen eerste en tweede generatie technieken (OR: 1.20, 95% CI :0.88 tot 1.62, p = 0.2), hoewel de tweede generatie technieken minder tijd kosten (GGV: 14.5 minuten, 95% CI :13.7 tot 15.3, p < 0.00001) en vrouwen sneller herstelden (GGV: 0.48 dagen, 95% CI :0.20 tot 0.75, p = 0.0008) en minder complicaties ondervonden. Meer vrouwen waren ontevreden na endometrium ablatie dan na hysterectomie. Echter, het percentage vrouwen dat ontevreden is, is laag na alle behandelingen, en hysterectomie wordt geassocieerd met een verhoogd verblijf in het ziekenhuis en herstelp- eriode. Definitief bewijs voor de effectiviteit van de LNG-IUS in vergelijking met meer invasieve procedures ontbreekt vooralsnog. In hoofdstuk 10 breidden we het review uit en evalueerden ook de relatieve effectiviteit van de tweede generatie ablatie technieken bij de behandeling van hevige menstruaties. Wij identifi- ceerden 19 gerandomiseerde gecontroleerde studies met 3287 vrouwen. Netwerk meta-analyse liet zien dat na 12 maanden bipolaire radiofrequente ablatie en microwave ablatie resulteerden in hogere amenorroe percentages dan thermische ballon ablatie (OR: 2.51, 95% CI 1.53 tot 4.12, p <0.001, en 1.66, 1.01 tot 2.71, p = 0.05, respectievelijk). Toch was er geen overtuigend verschil tussen de drie technieken in het aantal vrouwen dat nog steeds ontevreden was over de be- handeling of nog steeds last had van hevig menstrueel bloedverlies. In vergelijking met bipolaire radiofrequente ablatie en microwave ablatie, was het aantal vrouwen dat met hevig menstrueel Chapter 12 185 bloedverlies na vrij vocht ablatie verhoogd (OR: 2.19, 95% CI 1.07 tot 4.50, p = 0.03, en 2.91, 1.23 tot 6.88, p = 0.02, respectievelijk ). In vergelijking met bipolaire radiofrequente ablatie, was vrij vocht ablatie geassocieerd met een verminderde kans op amenorroe (OR: 0.36, 95% CI 0.19 tot 0.67, p = 0.004) en een verhoogde mate van ontevredenheid (OR: 4.79, 95% CI 1.07 tot 21.5, p = 0.04). Wij concludeerden dat bipolaire radiofrequente ablatie en microwave ablatie ef- fectiever zijn dan thermische ballon ablatie in de behandeling van heftig menstrueel bloedverlies met tweede generatie ablatie apparaten. Ten slotte, werd in hoofdstuk 11 de betrouwbaarheid en validiteit van de Menorragie Multi-At- tribute Scale (MMAS), een menorragie-specifieke kwaliteit van leven instrument, onderzocht. De MMAS bleek goede meet eigenschappen te hebben en is daarom een geschikt conditie-speci- fiek instrument om de uitkomst van de behandeling van heftig menstrueel bloedverlies te meten. Summary and Discussion 186

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Cochrane Database of Systematic Reviews 2012. 37 Shapley M, Jordan K, Croft PR. An epidemiological survey of symptoms of menstrual loss in the community. Brit Gen Pract 2004;54(502):359-63. 38 Office of Population Census and Surveys. Morbidity Statistics from General Practice. Lon- don: HMSO; 1995. Report No.: Fourth National Morbidity Study 1991-1992. 39 National Collaborating Centre for Women’s and Children’s Health. Heavy Menstrual Bleeding. 2008. 40 Santer M, Wyke S, Warner P . What aspects of periods are most bothersome for women reporting heavy menstrual bleeding? Community survey and qualitative study. BMC Wo- mens Health 2007;7:8. 41 Pattison H, Daniels JP , Kai J, Gupta JK. The measurement properties of the menorrhagia multi-attribute quality-of-life scale: a psychometric analysis. BJOG 2011;118(12):1528-31. 42 Shaw RW, Brickley MR, Evans L, Edwards MJ. Perceptions of women on the im- pact of menorrhagia on their health using multi-attribute utility assessment. BJOG 1998;105(11):1155-9. Chapter 12 189

Chronic Pelvic Pain Daniels, J, Khan, K.S. BMJ 2010;341:c4834 Laparoscopic uterine nerve ablation: a survey of gynaecological practice in the UK Daniels J, Gray R, Khan KS, Gupta JK. Laparoscopic uterine nerve ablation: A survey of gynae- cological practice in the UK. Gynaecol Endoscopy 2000; 9:157-159. A randomised controlled trial to assess the efficacy of Laparoscopic Uterosacral Nerve Ablation in the treatment of chronic pelvic pain: the trial protocol A randomised controlled trial to assess the efficacy of Laparoscopic Uterosacral Nerve Ablation (LUNA) in the treatment of chronic pelvic pain: The trial protocol [ISRCTN41196151]. BMC Wo- mens Health 2003;3(1):6. A randomized controlled trial to assess the effectiveness of Laparoscopic Uterosacral Nerve Ablation for alleviating chronic pelvic pain Daniels J, Gray R, Hills RK, Buckley L, Gupta JK, Latthe P , et al on behalf of the LUNA Trial Col- laboration A Randomized Controlled Trial to Assess the Effectiveness of Laparoscopic Uterosa- cral Nerve Ablation (LUNA) for alleviating Chronic Pelvic Pain JAMA 2009;302(9):955-961 Meta-analysis using individual patient data from randomised trials to assess the effec- tiveness of Laparoscopic Uterosacral Nerve Ablation in the treatment of chronic pelvic pain: a proposed protocol. Xiong T, Daniels J, Middleton L, Champaneria R, Khan KS, Gray R, et al International LUNA IPD Meta-analysis Collaborative Group Meta-analysis using individual patient data from randomised trials to assess the effectiveness of laparoscopic uterosacral nerve ablation in the treatment of chronic pelvic pain: a proposed protocol. BJOG. 2007 Dec;114(12):1580, e1-7 Individual patient data meta-analysis to assess the effectiveness of laparoscopic uter- osacral nerve ablation in the treatment of chronic pelvic pain. Daniels JP , Middleton L, Xiong X, Champaneria R, Johnson NP , Lichten EM, Sutton C, Vercellini P ,, Gray R, Hills RK, Jones KD, Aimi G, Khan KS. Individual patient data meta-analysis to assess the effectiveness of laparoscopic uterosacral nerve ablation in the treatment of chronic pelvic pain. Hum Reprod Update doi: 10.1093/humupd/dmq031

190 Psychological therapies for chronic pelvic pain: systematic review of randomised con- trolled trials Champaneria R, Daniels JP , Raza A, Pattison HM, Khan KS. Psychological Therapies for Chron- ic Pelvic Pain: Systematic review of Randomised Controlled Trials. Acta Obs Gynae Scand 2012;91(3):281-6 Hysterectomy, endometrial destruction and Mirena ® for heavy menstrual bleeding: a systematic review and individual patient data meta-analysis Middleton L, Champaneria R, Daniels J, Bhattachayra S, Cooper K, Khan KS Hysterectomy, endometrial destruction and Mirena® for heavy menstrual bleeding: a systematic review and individual patient data meta-analysis. BMJ 2010; 341:c3929 Hysterectomy, endometrial ablation, and levonorgestrel releasing intrauterine system (Mirena) for treatment of heavy menstrual bleeding: cost effectiveness analysis Roberts TE, Tsourapas A, Middleton LJ, Champaneria R, Daniels JP , Cooper KG, Bhattacha- rya S, Barton PM. Hysterectomy, endometrial ablation, and levonorgestrel releasing intrauterine system (Mirena) for treatment of heavy menstrual bleeding: cost effectiveness analysis. BMJ. 2011;342:d2202 Second generation endometrial ablation techniques for heavy menstrual bleeding: a network meta-analysis. Daniels JP , Middleton LJ, Champaneria R, Khan KS, Cooper K, Moll BW, Bhattacharya S. Sec- ond generation endometrial ablation techniques for heavy menstrual bleeding: a network meta- analysis. BMJ. 2012 Apr 23;344:e2564 The measurement properties of the menorrhagia multi-attribute quality-of-life scale. a psychometric analysis. Pattison H, Daniels J, Kai J, Gupta JK. BJOG 2011;118:1528–1531. Other publications 1. Gupta J.K., Kai J, Middleton LJ, Pattison H, Gray R., Daniels JP , on behalf of the ECLIPSE Collaborative Group. Levonorgestrel intrauterine system versus medical therapy for men- orrhagia. NEJM 2013; 368:128-137 2. Champaneria R, Shah L, Geoghegan J, Gupta JK, Daniels JP . Analgesic effectiveness of transversus abdominis plane blocks after hysterectomy: a meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2012 Oct 4. doi: 10.1016/j.ejogrb.2012.09.012.

191 3. Gray JW, Milner PJ, Edwards EH, Daniels JP , Khan KS. Feasibility of using microbiology diagnostic tests of moderate or high complexity at the point - of - care in a delivery suite. J Obstet Gynaecol. 2012;32(5):458-60. 4. Powell R, Pattison H, Bhoyar A, Furmston AT, Middleton LJ, Daniels JP , Ewer A. Pulse oximetry screening for congenital heart defects in newborn infants: an evaluation of ac- ceptability to mothers. Arch Dis Child Fetal Neonatal Ed. 2013;98: F59-63. 5. Ewer AK, Middleton LJ, Furmston AT, Bhoyar A, Daniels JP , Thangaratinam S, Deeks JJ, Khan KS; PulseOx Study Group. Pulse oximetry screening for congenital heart defects in newborn infants (PulseOx): a test accuracy study. Lancet. 2011 Aug 27;378(9793):785-94 6 Bhattacharya S, Middleton L, Tsourapas A, Lee A, Champaneria R, Daniels J, Roberts T, Hilken N, Barton P , Gray R, Khan K, Chien P , O’Donovan P , Cooper K; the International Heavy Menstrual Bleeding Individual Patient Data Meta-analysis Collaborative Group. Hysterectomy, endometrial ablation and Mirena® for heavy menstrual bleeding: a sys- tematic review of clinical effectiveness and cost-effectiveness analysis. Health Technol Assess. 2011 Apr;15(19):1-25. 7. Roberts TE, Tsourapas A, Middleton LJ, Champaneria R, Daniels JP , Cooper KG, Bhat- tacharya S, Barton PM. Hysterectomy, endometrial ablation, and levonorgestrel releasing intrauterine system (Mirena) for treatment of heavy menstrual bleeding: cost effectiveness analysis. BMJ. 2011;342:d2202. 8. Clark TJ, Samuel N, Malick S, Middleton LJ, ,Daniels JP , Gupta JK Bipolar radiofrequency compared with thermal balloon endometrial ablation in the office: a randomized controlled trial Obstet Gynaecol 2011;117(1):109-18 . 9. Daniels JP , Gray J, Pattison H, Gray R, Hills RK, Khan KS Intrapartum tests for Group B Streptococcus: Accuracy and acceptability of screening. BJOG 2011;118(2):257-65. 10. Kaambwa B; Bryan B; Gray J; Milner P; Daniels J; Khan KS; Roberts T. Cost-Effective- ness Of Rapid Tests And Other Existing Strategies For Screening And Management Of Early Onset Group B Streptococcus During Labour. BJOG 2010;117(13):1616-2. 11. Champaneria R, Abedin P , Daniels J, Balogun M, Khan KS Magnetic resonance imaging and ultrasound scan for the diagnosis of adenomyosis: Systematic review of test accu- racy Acta Scand Obs Gynae 2010. 89(11):1374-84. 12. Brown C, Morris RK, Daniels J, Khan KS, Lilford RJ, Kilby MD.Effectiveness of percutane- ous vesico-amniotic shunting in congenital lower urinary tract obstruction: divergence in prior beliefs among specialist groups.Eur J Obstet Gynecol Reprod Biol. 2010;152(1):25-9. 13. Williams A, Gill S, Varma T, Jenkinson C, Quinn N, Mitchell R, Scoot, R, Ives N, Rick C, Daniels J, Patel S, Wheatley K on behalf of the PD SURG Collaborative Group Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson’s disease (PD SURG trial): a randomised, open-label trial. Lancet Neurol. 2010 9(6):581-91.

192 14. Thomas KS on behalf of the UK Dermatology Clinical Trials Network’s PATCH study group. Studying a disease with no home--lessons in trial recruitment from the PATCH II study. Trials. 2010;11:22. 15. ASTRAL Collaboration Revascularisation versus medical therapy for renal-artery stenosis. N Eng J Med 2009;361(20)1951-62. 16. Daniels J; Gray J, Pattison H, Roberts T, Edwards E; Milner P et al Rapid testing for GBS during labour: a test accuracy study with evaluation of acceptability and cost-effective- ness. Health Technol Assess 2009;13(42). 17. Geoghegan J, Daniels JP , Moore PAS, Thompson PJ, Khan KS, Gulmezoglu AM Cell Salvage at Caesarean Section: The need for an evidence based approach. BJOG 2009 116(6):743-7. 18. Ainsworth R, Dziedzic K, Hiller L, Daniels J, Bruton A, Broadfield J A prospective double blind placebo-controlled randomised trial of ultrasound in the physiotherapy treatment of shoulder pain Rheumatology 2007; 46: 815-820. 19. Thangaratinam S, Daniels J, Ewer AK, Zamora J, Khan KS. The accuracy of pulse oxi- metry in screening for congenital heart disease in asymptomatic newborns: A systematic review. Arch Dis Child. 2007; 92:F176-F180. 20. Kilby MD; Daniels JP; Khan K Congenital lower urinary tract obstruction: To shunt or not to shunt? Brit J Urol 2006; 97(1):6-8. 21. Dziedzic K, Hill J, Lewis M, Sim J, Daniels J, Hay EM. Effectiveness of manual therapy or pulsed shortwave diathermy in addition to advice and exercise for neck disorders: a pragmatic randomized controlled trial in physical therapy clinics. Arthritis Rheum 2005; 53(2):214-222. 22. Latthe PM, Powell RJ, Daniels J, Hills RK, Gray R, Gupta JK et al. Variation in practice of laparoscopic uterosacral nerve ablation: a European survey. Journal of Obstetrics and Gynaecology 2004; 24(5):547-51. 23. Stowe RL, Wheatley K, Clarke CE, Ives NJ, Hills RK, Williams AC et al. Surgery for Parkin- son’s disease: lack of reliable clinical trial evidence. J Neurol Neurosurg Psychiatry 2003; 74(4):519-521. 24. Clark TJ, Daniels J, Khan KS, Gupta JK. Hysterectomy with bilateral salpingo-oopho- rectomy: A survey of gynaecological practice in the UK. Acta Obs Gynae Scand 2001; 80(1):62-64. 25. Adams CE, Gray R, Daniels J, Thornley B, Philpott H, Wahlbeck K. Are UK consultants interested in pragmatic trials for those with schizophrenia? Schizophrenia Research 41, 233. 2000.

193 Authors’ affiliations Elizabeth Adey Research Manager, Birmingham Heartlands Hospital, UK Formerly, Birmingham Clinical Trials Unit, University of Birmingham, UK Giorgio Aimi Gynaecologist, University of Milan, Italy Siladitya Bhattacharya Professor of Obstetrics and Gynaecology, University of Aberdeen, UK Laura Buckley Medical Statistician, CRUK Clinical Trials Unit, University of Birmingham, UK Formerly, Birmingham Clinical Trials Unit, University of Birmingham, UK Rita Champaneria Research Fellow, Birmingham Clinical Trials Unit, University of Birmingham, UK FP Chen Gynaecologist, Keelung Chang Gung Memorial Hospital, Keeling, Taiwan Kevin Cooper Consultant in Obstetrics and Gynaecology, Aberdeen Royal Infirmary, UK Michael Gannon Consultant in Obstetrics and Gynaecology, Midland Regional Hospital, Mulligar, Republic of Ireland Richard Gray Professor of Medical Statistics, Clinical Trial Service Unit, University of Oxford, UK Formerly, Birmingham Clinical Trials Unit, University of Birmingham, UK Janesh Gupta Professor of Obstetrics and Gynaecology, University of Birmingham, UK Nicholas Hilken IT Coordinator, Birmingham Clinical Trials Unit, University of Birmingham, UK Robert K Hills Senior Lecturer in Translational Statistics, Department of Haematology, Cardiff University, UK Formerly, Birmingham Clinical Trials Unit, University of Birmingham, UK Neil Johnson Associate Professor, University of Auckland, New Zealand Kevin Jones Consultant Gynaecologist, Great Western Hospital, Swindon, UK Joe Kai Professor of Primary Care, University of Nottingham, UK Khalid S Khan Professor of Women’s Health, Blizzard Institute, Queen Mary University London, UK Formerly, Academic Department of Obstetrics and Gynaecology, University of Birmingham, UK Author’s affiliations 194 Pallavi Latthe Consultant Urogynaecologist, Birmingham Women’s Hospital, UK Edward Lichten Gynaecologist, Birmingham, Michigan, USA Richard Lilford Professor of Clinical Epidemiology, University of Birmingham, UK WM Lui Gynaecologist, Taipei Medical University Hospital, Taiwan Lee Middleton Senior Medical Statistician, Birmingham Clinical Trials Unit, University of Birmingham, UK Ben Willem Mol Professor of Obstetric, Gynaecology and Clinical Epidemiology, Academisch Medisch Centrum, Amsterdam, Netherlands Peter O’Donovan Professor of Medical Innovation, University of Bradford, UK Helen Pattison Professor of Health Psychology, Aston University, Birmingham, UK Amer Raza Consultant in Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, UK Tara Selman Specialist Registrar, Birmingham Women’s Hospital, UK Christopher Sutton Consultant Gynaecologist, Guildford Nuffield Hospital, UK Paolo Vercellini Associate Professor, University of Milan, Italy Tengbin Xiong Research Fellow, University of East Anglia, UK Formerly, Department of Public Health, University of Birmingham, UK Author’s affiliations 195 Dankwoord (Acknowledgements) Those that know me will know that it has taken a long time and a roundabout route to get to the end of this thesis and the opportunity to defend it. This is the end of a journey started many years ago, with several detours and dead-ends, but that has ultimately brought me great satisfaction. I am privileged to have a career that can improve the lives of women worldwide, and that brings me such satisfaction. There are a number of people who have helped and supported me along the way, and I want to thank them all now, and hope I have not forgotten anyone. First, my supervisor Professor Khalid Khan. I sincerely believe most of the best opportunities I have had in my career in clinical research have been due to Khalid. We both arrived in Birming- ham at about the same time: he with a trial in need of trials unit support, me embarking on a change of direction from laboratory research. Together we learnt the art and science of clinical trial research from Professor Richard Gray (more of whom later) in the completion of the LUNA Trial. In the following years, Khalid has helped broaden my methodological repertoire, my network of collaborators and my way of thinking about science and society. I thank you for your patience, wisdom, generosity, general chilled-outness. More than anything else though, you gave me the belief that I could finally achieve this PhD and for that I am so grateful. Very many thanks go to Professor Doctor Ben Willem Mol, my Dutch promoter. I was introduced to Ben Willem by Khalid over an expensive meal and believe this was one of the most fortuitous meetings in my life. Although I have not been one of your “traditional” PhD students, I have learnt a lot from your approach to clinical research. I am grateful for the opportunity to work in the de- partment and the seminars you made me present, and wish that I could have spent more time in Amsterdam. Your research consortium has established the Netherlands as a major player in women’s health research and Holland’s loss will be Australia’s gain. The other major influence in my career has been Professor Richard Gray, formerly Director of the Birmingham Clinical Trials Unit (BCTU), to whom I will be forever grateful. From you, I learnt that trial should be large and simple, systematic reviews are great for quickly getting to know a sub- ject and meta-analyses are never as easy as they sound. I intend to maintain the high standard of trials research you established at Birmingham and create a legacy for research at Birmingham Women’s Hospital. I would like to remember the LUNA Trial team, including Khalid, Richard, Liz Adey, Pallavi Latthe, Tara Selman, Janesh Gupta, Robert Hills, Laura Buckley, Becky Gair, Becky Powell and Leanne Lynch amongst others. LUNA was a great trial run on a shoe-string, compared to more recent Dankwoord (Acknowledgements) 196 projects, so it shows what great teamwork can do. LUNA also proves that surgeons can ran- domise and surgical trials can be blinded, and undoubtedly laid the foundations for other BCTU gynaecological studies. I thank the clinical investigators who recruited their patients and all the women, who in looking for a solution to their pain, agree to participate. Another big thank-you goes to the Heavy Menstrual Bleeding Individual Patient Data Meta-Analy- sis Collaborative group, including Bhatty, Khalid, Richard, Kevin Cooper, Rita Champaneria, Nick Hilken, Lee Middleton, Tracy Roberts and all the primary study authors. Never let it be said that IPD meta-analyses are easy, but working together with this team made it enjoyable and interest- ing, and started a great partnership with University of Aberdeen. I’d also like to acknowledge the ECLIPSE team, including Janesh Gupta, Joe Kai, Laura Gennard and Lisa Leighton but particularly Helen Pattison. It is important to know how to ask the right questions, if we are to get the right answers, and together we pondered over the MMAS scale and the definition of a psychological therapy. I thank the Promotion Committee, who have graciously allowed me to proceed to defend my thesis in public and who will come from Aberdeen and Veldhoven and all points in-between to the defence ceremony. My thanks go to Professor Dr P .M.M Bossuyt, Dr J.P .W.R. Roovers, Dr M.Y. Bongers, Professor Dr R.J. Lilford, Dr W.M. Ankum and Professor Dr S. Bhattachayra. Huge thanks go to my paranymphs Merel Breijer, who is teaching me the etiquette of Dutch defence ceremonies and Lee Middleton, who doesn’t yet know what he has let himself in for. I would like to mention all the staff of the Birmingham Clinical Trials Unit, who continue to work extremely hard to design and deliver clinical trials to the highest standard, and in particular the past and present members of the Women’s Health team. The BCTU is not only responsible for producing much important data which is changing people’s lives, but is also a great place to work. I am so proud of the work we all do. I really want to thank my old friends Harry, Shona, Laura, Donna and Jon who have seen me through the years and waited so patiently for the post-PhD party; Mum and Dad, who although will not be there to see the ceremony, I know are suitably proud of their daughter, and last but not least, my husband Pete. I simply could not have done this without your love. Dankwoord (Acknowledgements) 197 Curriculum vitae Name PhD student: Jane Daniels PhD period: 2011 -2013 Name PhD supervisor: prof dr B.W.J. Mol, prof dr K.S. Khan 1. PhD training Year Workload (Hours) General courses - None Specific courses - None Seminars, workshops and master classes - Departmental seminars at AMC - Internal seminars at the University of Birmingham Clinical Trials Unit, Departments of Public Health and Obstetrics and Gynaecology 2011 2011 2012 1.5 4 4 Presentations - Internal seminars at University of Birmingham Clinical Trials Unit - Trial specific presentations at trial collaborators’ meetings 2011, 2012 2011, 2012 2 1 1 2 (Inter)national conferences - Joint British and European Society of Gynaecological Endoscopy, London. Invited oral presentation - Cochrane Colloquium, Madrid. Poster presentation - British Society of Gynaecological Endoscopy, Cardiff. Selected oral presentation - European Society of Gynaecological Endoscopy, Paris. Invited oral presentation - GLOW Conference, Liverpool. Invited oral presentation - British Society of Gynaecological Endoscopy, Brighton. Invited oral presentation 2011 2011 2012 2012 2012 2013 30 38 30 30 22 30 Other Curriculum vitae 198 2. Teaching Year Workload (Hours/ ECTS) Lecturing - Research Methods for Clinical Trials, University of Birmingham (triannual) - - MSc Public Health, University of Birmingham 2011 2012 2013 2011 2012 3 3 0.5 3 3 Tutoring, Mentoring - MBChB Personal Mentor, 1st and 2nd year undergraduates (6 students) 2011 2012 2013 15 15 5 Supervising - Team leader for 12 members of staff within University of Birmingham, Clinical Trials Unit. Ongoing Other - Data Monitoring Committee member: EASEBACK trial 2012 3 3. Parameters of Esteem Year Grants 1. National Institute for Health Research, Health Technology Assesment Programme. The relationship between refluxing pelvic veins and chronic pelvic pain in women. 2. Medical Research Council/ Department for International Development/Wellcome Trust. AIMS: The Antibiotics in Miscarriage Surgery Trial. 3. National Institute for Health Research, Health Technology Assesment Programme. Preventing Recurrence of Endometriosis by Means of long acting Protestogen Therapy: PREEMPT Trial 2011 2012 2012 Awards and Prizes - Curriculum vitae 199